WO2011004972A2 - Piperazinyl 3-aminopyrrolidine derivatives as a ccr2 antagonist - Google Patents

Piperazinyl 3-aminopyrrolidine derivatives as a ccr2 antagonist Download PDF

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WO2011004972A2
WO2011004972A2 PCT/KR2010/003790 KR2010003790W WO2011004972A2 WO 2011004972 A2 WO2011004972 A2 WO 2011004972A2 KR 2010003790 W KR2010003790 W KR 2010003790W WO 2011004972 A2 WO2011004972 A2 WO 2011004972A2
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methyl
carbamoyl
pyrrolidin
piperazin
ethyl
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PCT/KR2010/003790
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French (fr)
Korean (ko)
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WO2011004972A3 (en
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임지웅
김종훈
옥민호
나용호
오유나
강소희
이정옥
손정덕
이승우
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양지화학 주식회사
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Priority to RU2012104633/04A priority Critical patent/RU2012104633A/en
Priority to BR112012000609A priority patent/BR112012000609A2/en
Priority to CA2767734A priority patent/CA2767734A1/en
Priority to CN201080031168.9A priority patent/CN102498109B/en
Priority to US13/383,104 priority patent/US8575173B2/en
Priority to JP2012519459A priority patent/JP5474189B2/en
Priority to EP10797246.5A priority patent/EP2452939B1/en
Publication of WO2011004972A2 publication Critical patent/WO2011004972A2/en
Publication of WO2011004972A3 publication Critical patent/WO2011004972A3/en

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    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to novel compounds useful as therapeutics for inflammation and various other diseases through chemokine receptor 2 (CCR2) antagonistic effects in vivo.
  • CCR2 chemokine receptor 2
  • the physiological action of the 3-aminopyrrolidine derivatives showing antagonism of CCR2 (chemokine receptor 2), a receptor of MCP-1 (monocyte chemotactic protein-1) was verified.
  • Chemokine is a physiologically active protein that mainly acts on the immune system in vivo, and about 50 kinds of substances have been identified so far. Are classified. Each chemokine binds to G-protein-coupled receptors (GPCRs) and exhibits their physiological activity. In particular, the receptor to which the CC chemokine MCP-1 binds is called CCR2. The function of MCP-1 is known to play an important role in the migration of monocytes in the inflammatory process (see Nature Review Drug Discovery, 2002, 1, 347).
  • MCP-1 and CCR2 have been identified in rheumatoid arthritis (Arthritis Rheum., 2001, 44, 2750), and extensive research by knockout mice has also been shown to result in MCP.
  • the roles of -1 and CCR2 have been validated (see Chemokine in Disease, 1999, 53-65).
  • CCR2 is regarded as a promising drug target of inflammatory diseases
  • CCR2 antagonistic effects can be used to develop therapeutics for various inflammation related diseases.
  • Johnson & Johnson has developed a dipiperidine compound, a CCR2 antagonist. This compound showed high binding to the CCR2 receptor and also blocked chemotaxis induced by MCP-1 in THP-1 cell line (WO 2006-036527, WO 2007-106797).
  • Millennium Corp. has also developed human monoclonal antibody MLN1202 against CCR2 as a therapeutic for inflammatory diseases, demonstrating that CCR2 is a promising drug target for inflammatory diseases by obtaining positive results in clinical studies of atherosclerosis.
  • Obesity and insulin resistance which are important features of metabolic syndrome, are closely related to inflammation.
  • Chronic overnourishment persists in macrophages in adipose tissue resulting in local inflammation, which intensifies insulin resistance.
  • Inhibiting MCP-1 or its receptor, CCR2 can inhibit the migration of macrophages to adipose tissue, thereby reducing the inflammation of adipose tissue and increasing insulin sensitivity.
  • Animal test results show that mice lacking CCR2 have a decreased diet compared to normal mice and that obesity does not develop even with high-fat diets (Nature, 2007, 447, 1116).
  • CCR2 also offers potential as a treatment for Alzheimer's disease.
  • CCR2 plays an important role in the migration of microglia (Nature Medicine, 2007, 13, 432).
  • the present invention is a novel compound comprising a piperazinylethyl 3-aminopyrrolidine structure, which is capable of strongly inhibiting the interaction of a monocyte chemotactic protein-1 (MCP-1) with a chemokine receptor 2 (CCR2). It is an object to provide a compound of the present invention, a pharmaceutically acceptable salt, optical isomer, hydrate, solvate and polymorph thereof.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing, treating or ameliorating CCR2-mediated inflammatory diseases and symptoms containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is independently a hydrogen atom, C 1 -C 3 alkyl, phenyl, benzyl, benzoyl, benzenesulfonyl, C 1 -C 3 alkylcarbonyl, C 3 -C 7 cycloalkyl,
  • R 10 , R 11 and R 12 can be independently selected from the group consisting of hydrogen atom, C 1 -C 3 alkyl, phenyl, and benzyl group;
  • All benzene groups included as part of R 1 may independently have a plurality of substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, a halogen atom, and a cyano group;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 can be independently selected from a hydrogen atom and C 1 -C 3 alkyl;
  • R 6 and R 7 , R 8 and R 9 can be independently selected from a carbonyl group
  • the halogen is selected from the group consisting of fluorine, chlorine and bromine atoms.
  • It may be a compound selected from the group consisting of.
  • the present invention may be in the form of a pharmaceutically acceptable salt, geometric or optical isomer, hydrate, solvate or polymorphic form of the compound of Formula 1.
  • the present invention is characterized in that the pharmaceutical composition for the prevention, treatment or amelioration of CCR2 (chemokine receptor 2) mediated inflammatory diseases and symptoms containing a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • CCR2 chemokine receptor 2
  • the pharmaceutical composition is characterized in that the vascular protective agent or immunosuppressive agent.
  • the CCR2-mediated inflammatory diseases and symptoms are allergic rhinitis, respiratory allergic diseases, chronic obstructive pulmonary disease, asthma, pneumonia, rheumatoid arthritis, uveitis, multiple sclerosis, contact dermatitis, atopic dermatitis, Crohn's disease, colitis, nephritis , Diabetes, diabetes complications, obesity, hyperlipidemia, arteriosclerosis and restenosis.
  • the present invention is characterized in that the compound of formula (1) or a pharmaceutically acceptable salt thereof is used as an anti-vascular or immunosuppressive agent.
  • the compound of the present invention having the formula (1) has a high affinity for the CCR2 receptor protein, and has been shown to effectively inhibit calcium influx and chemotaxis even in a low concentration range.
  • the inhibitory effect on CYP450 was relatively low, and it was confirmed that the compound is a safe compound having little cardiac toxicity and cytotoxicity.
  • the compounds of the present invention can be usefully used to treat, prevent or ameliorate various diseases related to rheumatoid arthritis, arteriosclerosis, multiple sclerosis, asthma and other CCR2.
  • the present invention provides compounds of formula (1), or isomers and pharmaceutically acceptable salts thereof, which exhibit CCR2 antagonistic effects.
  • R 1 is independently a hydrogen atom, C 1 -C 3 alkyl, phenyl, benzyl, benzoyl, benzenesulfonyl, C 1 -C 3 alkylcarbonyl, C 3 -C 7 cycloalkyl,
  • R 10 , R 11 and R 12 can be independently selected from the group consisting of hydrogen atom, C 1 -C 3 alkyl, phenyl, and benzyl group;
  • All benzene groups included as part of R 1 may independently have a plurality of substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, a halogen atom, and a cyano group;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 can be independently selected from a hydrogen atom and C 1 -C 3 alkyl;
  • R 6 and R 7 , R 8 and R 9 can be independently selected from a carbonyl group
  • the halogen is selected from the group consisting of fluorine, chlorine and bromine atoms.
  • the present invention relates to a compound of Chemical Formula 1, which exhibits a therapeutic effect against various diseases related to CCR2 through antagonizing the interaction of MCP-1 and CCR2 receptors, thereby controlling anti-inflammatory and immune function.
  • Pharmaceutically acceptable salts refer to acid addition salts or base addition salts which can be prepared by conventional organic synthesis methods depending on the specific functional groups of the compounds presented herein. At this time, the added acid or base is harmless to the human body or relatively less toxic and can be used in the manufacture of a drug. If the compounds of the present invention are basic, an appropriate amount of acid must be added for the salt to form.
  • Preferred acid addition salts include inorganic acids such as hydrochloric acid, bromic acid, nitric acid, sulfuric acid and iodic acid, acetic acid, citric acid, fumaric acid, galactamic acid, malonic acid, maleic acid, succinic acid, tartaric acid, methanesulfonic acid, lactic acid, oxalic acid and propionic acid.
  • Organic acids such as salicylic acid, mandelic acid, and phthalic acid.
  • Preferred base addition salts here include ammonium, sodium, potassium, calcium, magnesium, organoammonium and the like.
  • the compounds presented in the present invention may be unsolvated or hydrates containing water or solvates including organic solvents used in a conventional organic synthesis process, and all of these anhydrides, hydrates or solvates are within the scope of the present invention. Seen to belong.
  • the compounds presented in the present invention may exhibit amorphous or multiple polymorphisms in a solid state, and all of these amorphous or respective polymorphisms are considered to be within the scope of the present invention.
  • the compounds of the present invention can be prepared in a number of ways by conventional organic synthesis techniques.
  • the 3-aminopyrrolidine structure commonly included in the compounds of the present invention can be introduced in a number of ways, depending on commercially available raw materials.
  • the compounds of the present invention can be synthesized according to the methods shown in Schemes 1 to 6 below.
  • Compound (2) can be synthesized by reacting Compound (1), which is a commercially available starting material, with basic glycine, an amino acid, under basic and aqueous conditions.
  • the method of reacting compound (3), which is a derivative of the chiral 3-aminopyrrolidine described above with compound (2), to form an amide bond can be made according to a number of known methods.
  • isobutyl chloroformate is exemplified as a method of activating the carboxylic acid of compound (2), wherein the base is N-methylmorpholine (NMM). ) Can be easily produced.
  • the N-benzyl group of compound (4) means a protecting group, which must deprotect the benzyl group in order to prepare N-alkylation and other N-substituents in the pyrrolidine structure.
  • compound (5) can be easily prepared using hydrogen gas under a palladium catalyst (Pd (OH) 2 ).
  • Pd (OH) 2 palladium catalyst
  • the method of Scheme 3 can also be used to prepare compound (9) as a CCR2 antagonist presented in the present invention.
  • compound (9) prepared according to the method of Scheme 1 as a starting material, an intermediate compound was reacted under basic conditions using an epoxy compound or chloroethanol derivative substituted with R 6 , R 7 , R 8 and R 9. 10) to manufacture.
  • R 6 , R 7 , R 8 and R 9 are as defined herein.
  • Intermediate compound (11) can be obtained from the ethanol derivative (10) by reacting with methanesulfonyl chloride (MSCl) under basic conditions, whereby the compound (11) is purified, separated or not purified as necessary, and the following reaction is carried out. You can proceed.
  • the intermediate (11) is reacted with a piperazine derivative (12) in which R 1 , R 2 , R 3 , R 4 and R 5 are substituted under basic conditions.
  • the piperazine derivative (12) used at this time may take the form of a hydrochloride salt as needed, and R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein.
  • an intermediate compound (13) is prepared by reacting under basic conditions using an epoxy compound or a chloroethanol derivative substituted with R 6 , R 7 , R 8 and R 9 .
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined herein.
  • Intermediate compound (14) can be obtained by reacting with mesyl chloride under basic conditions from ethanol derivative (13), which compound (14) can be subjected to the next reaction without purification, separation or purification as necessary.
  • Intermediate (14) is reacted with pyrrolidine intermediate (5) under basic conditions to produce compound (9) desired in the present invention.
  • an intermediate compound (15) is prepared under basic conditions using a 2-chloroketone derivative substituted with R 6 , R 7 and R 8 .
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein.
  • the intermediate compound (15) can be subjected to reductive amination reaction with the pyrrolidine intermediate (5) to produce the target compound (9).
  • the reducing agent used may be variously selected according to a number of known methods, but in the present specification, N-alkyl using sodium triacetoxyborohydride (NaBH (OAc) 3 ), which is a relatively low reducing agent, is used.
  • NaBH (OAc) 3 sodium triacetoxyborohydride
  • R 6 and R 7 , R 8 and R 9 of Formula 1 as defined herein independently include a carbonyl group, and such a compound (20) as a CCR2 antagonist may be prepared according to the method illustrated in Scheme 6 below. .
  • R 8 and R 9 are formed under basic conditions, starting with piperazine (16) protected with a t-butoxycarbonyl group (Boc) and substituted with R 2 , R 3 , R 4 and R 5 .
  • Compound (17) is prepared by reaction with a substituted 2-chloroacetyl chloride derivative. Wherein R 2 , R 3 , R 4 , R 5 , R 8 and R 9 are as defined herein.
  • Compound (18) can be prepared from compound (17) via an intermediate reaction with intermediate (5) under basic conditions, and the protecting group is removed under acidic conditions under a suitable solvent to give compound (19).
  • Various halogen reagents can be prepared from intermediate compound (19) to prepare compound (20) as a CCR2 antagonist set forth in the present invention.
  • the compounds of the present invention can treat a number of diseases and symptoms by inhibiting the function of the CCR2 receptor. More specifically, for use in preventing, treating and ameliorating inflammatory diseases, disorders and symptoms mediated by CCR2. In another aspect, to inhibit or regulate activation of CCR2 thereby for diseases and symptoms associated with or overexpression of MCP-1.
  • Related diseases include inflammation and autoimmune diseases, specifically allergic rhinitis, respiratory allergic disease, chronic obstructive pulmonary disease, asthma, pneumonia, rheumatoid arthritis, uveitis, multiple sclerosis, contact dermatitis, atopic dermatitis, Crohn's disease Contains colitis, nephritis.
  • Metabolic diseases also include diabetes, diabetes complications, obesity, hyperlipidemia. In addition, it may be used for atherosclerosis and restenosis as a blood vessel-related disease, and may also be used for other vascular protective agents. It can also be used as an immunosuppressive agent for rejection of organ transplantation.
  • the compounds presented in the present invention can be used for both diseases and symptoms due to the pathological role of the CCR2 receptor.
  • the use as a therapeutic or symptomatic alleviator for such diseases and conditions is not limited to those described herein.
  • the compound presented in the present invention is an active ingredient as a CCR2 antagonist, and the daily oral dose of this active ingredient is in the range of 0.01 mg to 1,000 mg / kg, preferably in the range of 0.1 mg to 100 mg. It is configured in a form suitable for the administration mode selected according to the disease and the administration target. That is, it may be administered according to the dosage regimen once to five times per day, and may be administered alone or in combination with other drugs as necessary.
  • the present invention relates to a pharmaceutical composition containing the compound of Formula 1.
  • the pharmaceutical composition includes tablets, effervescent tablets, capsules, granules, powders, sustained-release tablets, sustained-release capsules and the like. It may also be administered as a pharmaceutical form, including formulations such as intravenous or intramuscular injections, suspensions, suppositories, skin patches, intraperitoneal injections, intranasal delivery devices, and the like, suitable for other active ingredients and administration purposes.
  • a preferred pharmaceutical composition using the compound of the present invention as an active ingredient it may be formulated to include physiologically resistant excipients, diluents, adjuvants, coating materials, antioxidants, aromatic substances.
  • excipients and auxiliaries include gelatin, sucrose, lactose, lecithin, pectin, starch, cyclodextrin, cyclodextrin derivatives, dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talc, ricoh
  • silicic acid calcium hydrogen phosphate, cellulose, methoxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, saturated or unsaturated fatty acids, vegetable glycerol esters, polyglycerol esters, alcohols, polyethylene glycols, Esters of aliphatic alcohols, glycols, g
  • supplements or disintegrants that may additionally be used are cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethylcellulose, microcrystalline cellulose. It is also possible to use tablet coatings, specific examples of which are ester polymers and copolymers of acrylic acid, methacrylic acid, methacrylic acid, zein, ethylcellulose, ethylcellulose succinate, shellac, citric acid esters, tartar esters, glycerol , Glycerol esters, polyethylene glycols. On the other hand, an appropriate amount of organic solvent may be used within water or a physiologically acceptable range for the preparation of the desired formulation or suspension.
  • preservatives, antioxidants and fragrance enhancers can be used, specific examples of which include potassium sorbate, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate, ascorbic acid, peppermint oil, and the like.
  • Solvents and emulsifiers such as polyvinylpyrrolidone, polysorbate 80, may be used as needed for preferred formulation.
  • Composition 1 (unit: mg per tablet)
  • Microcrystalline Cellulose 60.00
  • Composition 2 (unit: mg per tablet)
  • Microcrystalline Cellulose 50.00
  • Composition 3 (unit: mg per tablet)
  • Microcrystalline Cellulose 50.00
  • the CCR2 antagonistic effects of the compounds presented herein can be verified by appropriate pharmacological tests. Specifically, the affinity between the compound of the present invention and the CCR2 receptor protein, or a cell-level test, shows that the chemotaxis inhibitory effect of immune cells and the calcium ion influx (Ca 2+ flux) in the cytoplasm by the compound of the present invention.
  • the inhibitory effect can be determined by quantitative analysis. More specific methods for each pharmacological test are as described below.
  • the affinity of a compound that binds to CCR2 and blocks the signaling of the receptor is measured using human recombinant recombinant CCR2 receptor (Perkinelmer, USA) and radioligand [ 125 I] -MCP1 (Perkinelmer, USA) expressed in CHO cells.
  • the buffer used for receptor binding assays uses 50 mM Hepes (pH 7.4) containing 5 mM MgCl 2 , 1 mM CaCl 2 and 0.5% BSA.
  • test drug In a [ 125 I] -MCP1 binding assay, test drug, CCR2 membrane (10 ⁇ g / well), and [ 125 I] -MCP1 were added to a 96-well plate to prepare a reaction mixture with a final volume of 0.25 ml and incubated at 27 ° C. for 60 minutes. . After incubation, the reaction was terminated by rapid filtration through a Wallac filtermat A GF / C glass fiber filter (Wallac, Finland), pre-soaked with 0.5% PEI using an Inotech harvester (Inotech) and cold 50 mM Tris-HCl (pH 7.4) Wash with buffer.
  • the filter is covered with MeltiLex, sealed in a sample bag, dried in an oven and counted with MicroBeta Plus (Wallac).
  • the receptor affinity of the compound was measured at a high concentration of 10 ⁇ M, and repeated experiments were performed twice in each of two test tubes at 7 to 8 concentrations for a compound having a relatively high affinity showing an inhibitory effect of 50% or more at 10 ⁇ M.
  • Receptor affinity (IC 50 ) is calculated by computer nonlinear regression (GraphPad Prism Program, San Diego, USA). D-Trp6-LHRH (1 ⁇ M) is used for nonspecific binding assays.
  • CCR2b transformed cells (HEK293 / CCR2b) were seeded on lysine-coated black-clear bottom plates, allowed to acclimate for 24 hours, replaced with serum free media-DMEM (SFM) and left overnight. The next day, Flour-4 (calcium dye, Molecular probe) is treated, placed in the incubator for 50 minutes, washed with calcium-free buffer solution and the compound is pretreated for 10-15 minutes. The signal resulting from the addition of MCP-1 is measured on a FlexStation II (Molecular device).
  • SFM serum free media-DMEM
  • Antagonistic effects of compounds on CCR2 function can be measured by leukocyte chemotaxis assays using appropriate cells.
  • Suitable cells include cell lines, recombinant cells or isolated cells that express CCR2 and exhibit chemotaxis induced by CCR2 ligands (eg, MCP-1).
  • the cell line used is THP-1 cells and THP-1 cells are grown in RPMI-1640 supplemented with 10% fetal bovine serum in a 37 ° C., 5% CO 2 incubator. Cell density is maintained between 0.5 x 10 6 cells / ml. MCP-1 induced chemotaxis was run in a 96-well chemotaxis chamber (Neuro Probe) and 30 ⁇ l of recombination hMCP-1 (10 ng / ml, R & D) or buffer alone was added to the lower chamber, for 15 minutes with various concentrations of test compound. 50 ⁇ l of pre-cultured THP-1 cells (4 ⁇ 10 6 cells / ml) are added to the upper chamber.
  • chemotaxis index is the ratio of the mean of cells migrated in the presence of MCP-1 and the mean of migrated cells in the absence of chemokines. % Inhibition is computed using the following formula (1).
  • the F sample is the fluorescence of the cells previously incubated with various concentrations of the test compound and transferred to the lower chamber 10 ng / ml MCP-1;
  • F MCP-1 is the fluorescence of cells preincubated with buffer-0.1% DMSO and shifted to 10 ng / ml;
  • F buffer is the fluorescence of cells that have been previously incubated with buffer-0.1% DMSO and spontaneously migrated to the buffer of the lower chamber.
  • Tests by the affinity protocol for the CCR2 receptor protein show that the compounds of the present invention have an IC 50 in the range of 1 nM to 10 ⁇ M.
  • the compound of the present invention has an IC 50 range of 1 nM to 10 ⁇ M for each test.
  • the effectiveness as a pharmaceutical active ingredient can be verified through appropriate pharmacological tests. Specifically, the CYP450 inhibition is evaluated to predict the interaction between drugs, and the binding force to the hERG K + ion channel is estimated to predict cardiac toxicity. Cytotoxicity tests on cell lines can be performed to predict the toxicity as a drug in advance.
  • Luciferin assay reagent is dissolved in buffer and a membrane of each CYP enzyme is prepared. 6.25 ⁇ l of the compound is prepared at 4 times the concentration, and 6.25 ⁇ l of the reaction mixture of the appropriate substrate and enzyme is added for each type of enzyme and left for 10 minutes. 12.5 ⁇ l of CYP enzyme NADPH regeneration reagent is added to the reaction for 30 minutes, and then 25 ⁇ l luciferin measuring reagent is added and reacted for 20 minutes to measure fluorescence in Fusion ⁇ .
  • Compounds as CCR2 antagonists presented in the present invention showed binding ability in the range of 10 ⁇ M or less to 50% of the concentration of the compound with respect to the five CYP450 enzymes described above in performing the CYP450 inhibitory evaluation. It can be seen that low.
  • the hERG K + ion channel (channel) binding capacity of the drug is performed by radioligand [ 3 H] Astemizole substitution assay (hERG binding screening).
  • the drug is added to a buffer containing hERG cell membrane (2.5 ⁇ g / well) and [ 3 H] -Astemizole (4 nM) to make a 0.2 ml reaction mixture, which is then reacted at room temperature for 60 minutes.
  • the compound exhibits a binding force in the range of 50% or less at a concentration of 10 ⁇ M of the compound and thus is a safe compound having little cardiac toxicity.
  • MTS (3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H on THP-1 cells -tetrazolium, inner salt, Promega, USA) method.
  • the MTS method is a sensitive method that can measure the viability, proliferation and activity of the cell and utilizes the ability of mitochondrial dehydrogenase to convert yellow MTS into insoluble formazan during metabolism of living cells.
  • THP-1 cells are grown in RPMI-1640 supplemented with 10% fetal bovine serum in 37 ° C., 5% CO 2 incubator. Cell density is maintained between 0.5 x 10 6 cells / ml.
  • THP-1 cells are dispensed in 96-well plates at 1 ⁇ 10 5 cells / ml, the test compounds are treated with 1, 10 ⁇ M and 20 ⁇ l of 317 ⁇ g / ml of MTS is treated 24 hours later. After 1 hour, the absorbance of the ELISA reader was measured at 490 nm, and the activity of the cell was calculated by using the absorbance of the formazan crystal of the experimental group for the control group as shown in Equation 2 below.
  • the present invention performed cytotoxicity tests on various cell lines, for example, HepG2, NIH 3T3, CHO-K1, HEK 293, and the test method thereof was the same as or similar to that described above. Can be done.
  • the cell viability of all types of cell lines in the 10 ⁇ M treated group of the test compound was 50% or higher, showing little cytotoxicity and a safe compound compared to the control group without the sample. have.

Abstract

The present invention relates to compounds of chemical formula 1, which exhibit antagonistic effects against chemokine receptor 2 (CCR2), and to salts or isomers thereof. The compounds are useful in treating, preventing, or improving rheumatoid arthritis, arteriosclerosis, multiple sclerosis, asthma and other CCR2-related diseases. R1, R2, R3, R4, R5, R6, R7, R8 and R9 in chemical formula 1 are identical to those expressed in the present specification.

Description

CCR2 길항제로서의 피페라지닐에틸 3-아미노피롤리딘 유도체 Piperazinylethyl 3-aminopyrrolidine Derivatives as CCR2 Antagonists
본 발명은 생체내 CCR2 (chemokine receptor 2) 길항 효과를 통해 염증 및 기타 다양한 질환에 대한 치료제로서 유용한 신규 화합물에 관한 것이다. 구체적으로, MCP-1 (monocyte chemotactic protein-1)의 수용체인 CCR2 (chemokine receptor 2)에 대한 길항 작용을 나타내는 3-아미노피롤리딘(3-aminopyrrolidine) 유도체의 활성 효과를 검증하여, 이러한 생리 작용과 관련된 질환, 예를 들어 류마티스 관절염, 동맥경화증, 다발성경화증, 천식 및 기타 CCR2에 관련된 여러 질환을 치료 또는 개선하는 데 유용한 신규 화합물을 제공한다.The present invention relates to novel compounds useful as therapeutics for inflammation and various other diseases through chemokine receptor 2 (CCR2) antagonistic effects in vivo. Specifically, the physiological action of the 3-aminopyrrolidine derivatives showing antagonism of CCR2 (chemokine receptor 2), a receptor of MCP-1 (monocyte chemotactic protein-1), was verified. Provided are novel compounds useful for treating or ameliorating diseases related to, for example, rheumatoid arthritis, arteriosclerosis, multiple sclerosis, asthma and other diseases associated with CCR2.
케모카인(chemokine)은 주로 생체내 면역 체계에 작용하는 생리활성 단백질로서 이제까지 50여종의 물질이 밝혀졌으며, 아미노산 서열상 공통적인 시스테인의 구조적 차이를 근거로 하여 C, CC, CXC 및 CX3C의 4가지로 분류된다. 각각의 케모카인은 GPCR(G-protein-coupled receptor)에 결합하여 그들의 생리작용을 나타내는데, 특히 CC 케모카인인 MCP-1이 결합하는 수용체를 CCR2라고 한다. MCP-1의 기능은 기본적으로 염증 유발 과정에서 단핵세포(monocyte)의 이동에 중요한 역할을 하는 것으로 알려져 있다 (참조 : Nature Review Drug Discovery, 2002, 1, 347). 예를 들면, 류마티스 관절염의 경우 MCP-1 및 CCR2가 과도하게 발현되는 것이 확인되었으며 (참조 : Arthritis Rheum., 2001, 44, 2750), 또한 넉아웃 마우스(knockout mouse)에 의한 광범위한 연구를 통해 MCP-1과 CCR2의 역할이 검증되었다 (참조 : Chemokine in Disease, 1999, 53-65).Chemokine (chemokine) is a physiologically active protein that mainly acts on the immune system in vivo, and about 50 kinds of substances have been identified so far. Are classified. Each chemokine binds to G-protein-coupled receptors (GPCRs) and exhibits their physiological activity. In particular, the receptor to which the CC chemokine MCP-1 binds is called CCR2. The function of MCP-1 is known to play an important role in the migration of monocytes in the inflammatory process (see Nature Review Drug Discovery, 2002, 1, 347). For example, overexpression of MCP-1 and CCR2 has been identified in rheumatoid arthritis (Arthritis Rheum., 2001, 44, 2750), and extensive research by knockout mice has also been shown to result in MCP. The roles of -1 and CCR2 have been validated (see Chemokine in Disease, 1999, 53-65).
CCR2는 염증 질환의 유망한 약물 표적으로 간주되기 때문에 CCR2 길항 효과를 통해 염증 관련 여러가지 질환의 치료제를 개발할 수 있다. 예를 들어, 존슨 앤 존슨 (Johnson & Johnson)사는 CCR2 길항제인 디피페리딘 화합물의 개발을 진행하였다. 이 화합물은 CCR2 수용체에 대한 높은 결합력을 보여주었으며, 또한 THP-1 세포주에서 MCP-1에 의해 유도된 주화성(chemotaxis)을 차단하였다 (참조 : WO 2006-036527, WO 2007-106797). 한편, 밀레니엄사는 역시 CCR2에 대한 인간 단일클론 항체 MLN1202를 염증성 질환에 대한 치료제로 개발하여, 동맥경화증을 대상으로 한 임상시험에서 긍정적인 결과를 얻음으로써 CCR2가 염증 질환의 유망한 약물 표적임을 입증하였다.Since CCR2 is regarded as a promising drug target of inflammatory diseases, CCR2 antagonistic effects can be used to develop therapeutics for various inflammation related diseases. For example, Johnson & Johnson has developed a dipiperidine compound, a CCR2 antagonist. This compound showed high binding to the CCR2 receptor and also blocked chemotaxis induced by MCP-1 in THP-1 cell line (WO 2006-036527, WO 2007-106797). Millennium Corp., on the other hand, has also developed human monoclonal antibody MLN1202 against CCR2 as a therapeutic for inflammatory diseases, demonstrating that CCR2 is a promising drug target for inflammatory diseases by obtaining positive results in clinical studies of atherosclerosis.
한편 대사증후군의 중요한 특징인 비만과 인슐린 저항성은 염증과 밀접한 관련이 있다. 만성적으로 과잉영양 상태가 지속되면 지방조직에서 대식세포가 침윤되어 국소적 염증이 초래되고 이는 인슐린 저항성을 강화시킨다. 이때 MCP-1이나 그 수용체인 CCR2를 저해하면 대식세포의 지방조직으로의 이동을 억제할 수 있으며 이를 통해 지방조직의 염증을 감소시키고 인슐린 감수성을 증대시킬 수 있다. 동물 시험 결과에 의하면, CCR2를 결핍시킨 마우스는 정상적인 마우스에 비해 식사량이 감소하고 고지방의 식사를 섭취하더라도 비만이 발달하지 못하는 변화를 관찰할 수 있다 (참조 : Nature, 2007, 447, 1116).Obesity and insulin resistance, which are important features of metabolic syndrome, are closely related to inflammation. Chronic overnourishment persists in macrophages in adipose tissue resulting in local inflammation, which intensifies insulin resistance. Inhibiting MCP-1 or its receptor, CCR2, can inhibit the migration of macrophages to adipose tissue, thereby reducing the inflammation of adipose tissue and increasing insulin sensitivity. Animal test results show that mice lacking CCR2 have a decreased diet compared to normal mice and that obesity does not develop even with high-fat diets (Nature, 2007, 447, 1116).
CCR2는 알츠하이머병에 대한 치료제로서의 가능성도 제공한다. 알츠하이머 환자들의 뇌에 형성되는 플라크(plaque) 형태의 단백질인 아밀로이드-베타(amyloid-beta)의 축적 과정은 뇌와 중추신경계의 면역세포인 소교세포(microglia)의 조절을 받는 염증 반응경로가 관련된 것으로 알려져 있다. CCR2는 이 소교세포의 이동에 중요한 역할을 한다 (참조 : Nature Medicine, 2007, 13, 432).CCR2 also offers potential as a treatment for Alzheimer's disease. The accumulation of amyloid-beta, a plaque protein in the brain of Alzheimer's patients, involves an inflammatory pathway under the control of microglia, the immune cells of the brain and central nervous system. Known. CCR2 plays an important role in the migration of microglia (Nature Medicine, 2007, 13, 432).
CCR2 수용체의 길항 작용을 나타내는 저분자 화합물 중에서 3-아미노피롤리딘을 핵심 구조로 가지는 것은 공지의 기술로서, 예를 들어 WO 2004-050024에 의하면 3-아미노피롤리딘에 시클로알칸이 결합된 대표적인 구조가 제시되었다. 또한 WO 2000-069432에 의하면 3-아미노피롤리딘에 알킬기가 결합되고 이것에 다시 아릴 또는 시클로알킬이 연결된 화합물이 제시되었다. 이러한 화합물의 대표적인 구조는 3-아미노-N-벤질피롤리딘으로서 이것의 CCR2 수용체에 대한 길항 작용을 보고한 바 있다.Among the small molecule compounds exhibiting antagonism of the CCR2 receptor, having 3-aminopyrrolidine as a core structure is a well-known technique. For example, according to WO 2004-050024, a representative structure in which a cycloalkane is bound to 3-aminopyrrolidine is known. Is presented. WO 2000-069432 also suggests compounds in which an alkyl group is bonded to 3-aminopyrrolidine, to which aryl or cycloalkyl is again connected. Representative structures of these compounds have been reported to antagonize their CCR2 receptor as 3-amino-N-benzylpyrrolidine.
또한 3-아미노피롤리딘 구조를 포함하는 보다 다양한 구조의 화합물로서 WO 2003-075853에 제시된 바와 같이 3-아미노피롤리딘의 탄소 원자에 아릴술폰기가 치환된 화합물이 공지되었다. 한편 WO 2007-053495, WO 2007-053498, WO 2007-053499에 의하면, 3-아미노피롤리딘에 결합된 구조로서 헤테로 원자를 포함하는 시클로알칸이 제시되기도 하였다.Also known as compounds of more diverse structures, including 3-aminopyrrolidine structures, compounds in which an arylsulphone group is substituted for a carbon atom of 3-aminopyrrolidine as shown in WO 2003-075853. Meanwhile, according to WO 2007-053495, WO 2007-053498 and WO 2007-053499, cycloalkanes containing hetero atoms as a structure bonded to 3-aminopyrrolidine have been suggested.
본 발명은 피페라지닐에틸 3-아미노피롤리딘 구조를 포함하는 신규 화합물로서, MCP-1 (monocyte chemotactic protein-1)과 CCR2 (chemokine receptor 2)의 상호 작용을 강력하게 억제할 수 있는 화학식 1의 화합물, 이의 약학적으로 허용 가능한 염, 광학 이성질체, 수화물, 용매화물 및 결정다형체를 제공하는 것을 그 목적으로 한다.The present invention is a novel compound comprising a piperazinylethyl 3-aminopyrrolidine structure, which is capable of strongly inhibiting the interaction of a monocyte chemotactic protein-1 (MCP-1) with a chemokine receptor 2 (CCR2). It is an object to provide a compound of the present invention, a pharmaceutically acceptable salt, optical isomer, hydrate, solvate and polymorph thereof.
또한, 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 CCR2 매개 염증성 질환 및 증상의 예방, 치료 또는 개선용 약학 조성물을 제공하는 것을 또 다른 목적으로 한다.Another object of the present invention is to provide a pharmaceutical composition for preventing, treating or ameliorating CCR2-mediated inflammatory diseases and symptoms containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 혈관보호제 또는 면역억제제로서의 용도를 제공하는 것을 또 다른 목적으로 한다.It is another object of the present invention to provide the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof as an anti-vascular or immunosuppressive agent.
상술한 바와 같은 목적을 달성하기 위한 본 발명의 화합물은 하기 화학식 1의 구조를 갖는 것을 특징으로 한다: The compound of the present invention for achieving the object as described above is characterized by having the structure of Formula 1:
화학식 1
Figure PCTKR2010003790-appb-C000001
 Formula 1
Figure PCTKR2010003790-appb-C000001
상기 화학식 1에서,In Chemical Formula 1,
R1는 독립적으로 수소 원자, C1 - C3 알킬, 페닐, 벤질, 벤조일, 벤젠술포닐, C1 - C3 알킬카르보닐, C3 - C7 시클로알킬, R 1 is independently a hydrogen atom, C 1 -C 3 alkyl, phenyl, benzyl, benzoyl, benzenesulfonyl, C 1 -C 3 alkylcarbonyl, C 3 -C 7 cycloalkyl,
화학식 2
Figure PCTKR2010003790-appb-C000002
 Formula 2
Figure PCTKR2010003790-appb-C000002
화학식 3
Figure PCTKR2010003790-appb-C000003
 Formula 3
Figure PCTKR2010003790-appb-C000003
, 및 , And
화학식 4
Figure PCTKR2010003790-appb-C000004
 Formula 4
Figure PCTKR2010003790-appb-C000004
로 이루어진 군에서 선택될 수 있고; It may be selected from the group consisting of;
R10, R11 및 R12는 독립적으로 수소 원자, C1 - C3 알킬, 페닐, 및 벤질기로 이루어진 군에서 선택될 수 있고; R 10 , R 11 and R 12 can be independently selected from the group consisting of hydrogen atom, C 1 -C 3 alkyl, phenyl, and benzyl group;
R1의 일부로서 포함되는 모든 벤젠기는 독립적으로 C1 - C3 알킬, C1 - C2 할로알킬, 할로겐 원자, 및 시아노기로 이루어진 군에서 선택되는 복수의 치환체를 가질 수 있고; All benzene groups included as part of R 1 may independently have a plurality of substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, a halogen atom, and a cyano group;
R2, R3, R4, R5, R6, R7, R8 및 R9는 독립적으로 수소 원자, 및 C1 - C3 알킬 중에서 선택될 수 있고; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 can be independently selected from a hydrogen atom and C 1 -C 3 alkyl;
R6과 R7, R8과 R9는 독립적으로 카르보닐기로 선택될 수 있고; R 6 and R 7 , R 8 and R 9 can be independently selected from a carbonyl group;
상기 할로겐이란 불소, 염소 및 브롬 원자로 이루어진 군에서 선택됨.The halogen is selected from the group consisting of fluorine, chlorine and bromine atoms.
또한, 본 발명의 상기 화학식 1의 화합물은 In addition, the compound of Formula 1 of the present invention
N-{[1-(2-(1-(페닐아미노카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (1- (phenylaminocarbonyl) -piperazin-4-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Chloromethylbenzamide,
N-{[1-(2-(1-(p-톨릴아미노카르보닐)-피페라진-4-일)-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (1- (p-tolylaminocarbonyl) -piperazin-4-yl) -ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide,
N-{[1-(2-(1-(4-클로로페닐아미노카르보닐)-피페라진-4-일)-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (1- (4-Chlorophenylaminocarbonyl) -piperazin-4-yl) -ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl}- 3-trifluoromethylbenzamide,
N-{[1-(2-(1-(메톡시카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (1- (methoxycarbonyl) -piperazin-4-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Chloromethylbenzamide,
N-{[1-(2-(1-(에톡시카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (1- (ethoxycarbonyl) -piperazin-4-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Chloromethylbenzamide,
N-{[1-(2-(4-벤조일피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-benzoylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide,
N-{[1-(2-(4-(2-메틸벤조일)피페라진-1-일)에틸)- 피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (2-methylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide,
N-{[1-(2-(4-(3-메틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (3-methylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide,
N-{[1-(2-(4-(4-메틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (4-Methylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide,
N-{[1-(2-(4-(4-플루오로벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (4-fluorobenzoyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Chloromethylbenzamide,
N-{[1-(2-(4-(4-시아노벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (4-cyanobenzoyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Chloromethylbenzamide,
N-{[1-(2-(4-(4-에틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (4-ethylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide,
N-{[1-(2-(4-(페닐술포닐)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (phenylsulfonyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
N-{[1-(2-(4-프로피오닐피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-propionylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide,
N-{[1-(2-(4-벤질피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-benzylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide,
N-{[1-(1-(4-벤조일피페라진-1-일)프로판-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (1- (4-benzoylpiperazin-1-yl) propan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
N-{[1-(3-(4-벤조일피페라진-1-일)부탄-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (3- (4-benzoylpiperazin-1-yl) butan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
N-{[1-(2-(4-벤조일피페라진-1-일)프로판-1-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-benzoylpiperazin-1-yl) propan-1-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
N-{[1-(1-(4-벤조일피페라진-1-일)부탄-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (1- (4- (Benzoylpiperazin-1-yl) butan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
N-{[1-(2-(4-벤조일피페라진-1-일)부틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-benzoylpiperazin-1-yl) butyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide,
N-{[1-(2-(4-벤조일피페라진-1-일)-2-메틸프로필)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-benzoylpiperazin-1-yl) -2-methylpropyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
N-{[1-(1-(4-벤조일피페라진-1-일)-2-메틸프로판-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (1- (4-Benzoylpiperazin-1-yl) -2-methylpropan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3- Trifluoromethylbenzamide,
N-{[1-(3-(4-(3-클로로페닐)피페라진-1-일)부탄-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (3- (4- (3-chlorophenyl) piperazin-1-yl) butan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide,
N-{[1-(1-(4-페닐피페라진-1-일)프로판-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (1- (1- (4-phenylpiperazin-1-yl) propan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
N-{[1-(1-(4-시클로헥실피페라진-1-일)프로판-2-일)-피롤리딘(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (1- (4- (cyclohexylpiperazin-1-yl) propan-2-yl) -pyrrolidin (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide,
N-{[1-(2-(4-(2-히드록시부틸)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (2-hydroxybutyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Chloromethylbenzamide,
N-{[1-(2-(4-(2-히드록시-2-메틸프로필)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (2-hydroxy-2-methylpropyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl}- 3-trifluoromethylbenzamide,
N-{[1-(2-(4-(2-히드록시-2-페닐에틸)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (2-hydroxy-2-phenylethyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl}- 3-trifluoromethylbenzamide,
N-{[1-(2-(4-(2-(4-클로로페닐)-2-히드록시에틸)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (2- (4-chlorophenyl) -2-hydroxyethyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl ] -Methyl} -3-trifluoromethylbenzamide,
N-{[1-(2-(4-벤조일피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-benzoylpiperazin-1-yl) -2-oxoethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
N-{[1-(2-(4-(4-메틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (4-Methylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide,
N-{[1-(2-(4-(4-에틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (4-ethylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide,
N-{[1-(2-(4-(3-메틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (3-Methylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide,
N-{[1-(2-(4-(2-메틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (2-Methylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide,
N-{[1-(2-(4-페닐피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-phenylpiperazin-1-yl) -2-oxoethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
N-{[1-(2-(4-(벤족시카르보닐)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, 및 N-{[1- (2- (4- (Benzooxycarbonyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3 -Trifluoromethylbenzamide, and
N-{[1-(2-(4-벤조일-2,5-디메틸피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-benzoyl-2,5-dimethylpiperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Rommethylbenzamide
로 이루어진 군에서 선택된 화합물일 수 있다.It may be a compound selected from the group consisting of.
또한, 본 발명은 상기 화학식 1의 화합물의 약학적으로 허용 가능한 염, 기하 또는 광학 이성질체, 수화물, 용매화물 또는 결정다형체 형태일 수 있다.In addition, the present invention may be in the form of a pharmaceutically acceptable salt, geometric or optical isomer, hydrate, solvate or polymorphic form of the compound of Formula 1.
한편, 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 CCR2 (chemokine receptor 2) 매개 염증성 질환 및 증상의 예방, 치료 또는 개선용 약학 조성물임을 특징으로 한다.On the other hand, the present invention is characterized in that the pharmaceutical composition for the prevention, treatment or amelioration of CCR2 (chemokine receptor 2) mediated inflammatory diseases and symptoms containing a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 상기 약학 조성물은 혈관보호제 또는 면역억제제인 것을 특징으로 한다.In addition, the pharmaceutical composition is characterized in that the vascular protective agent or immunosuppressive agent.
또한, 상기 CCR2 매개 염증성 질환 및 증상은 알레르기성 비염, 호흡기성 알레르기 질환, 만성 폐쇄성 폐질환, 천식, 폐렴, 류마티스성 관절염, 포도막염, 다발성 경화증, 접촉성 피부염, 아토피성 피부염, 크론씨병, 대장염, 신염, 당뇨병, 당뇨 합병증, 비만, 고지혈증, 동맥경화증 및 재협착증으로 이루어진 군으로부터 선택될 수 있다.In addition, the CCR2-mediated inflammatory diseases and symptoms are allergic rhinitis, respiratory allergic diseases, chronic obstructive pulmonary disease, asthma, pneumonia, rheumatoid arthritis, uveitis, multiple sclerosis, contact dermatitis, atopic dermatitis, Crohn's disease, colitis, nephritis , Diabetes, diabetes complications, obesity, hyperlipidemia, arteriosclerosis and restenosis.
한편, 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 혈관보호제 또는 면역억제제로서의 용도임을 특징으로 한다.On the other hand, the present invention is characterized in that the compound of formula (1) or a pharmaceutically acceptable salt thereof is used as an anti-vascular or immunosuppressive agent.
화학식 1을 갖는 본 발명의 화합물은 상기 CCR2 수용체 단백질에 대해 친화력이 높고, 낮은 농도 범위에서도 칼슘 유입 및 화학 주성을 효과적으로 억제하는 것으로 나타났다. 그리고, CYP450에 대한 저해도가 비교적 낮으며, 심장 독성과 세포 독성이 거의 없는 안전한 화합물임을 확인할 수 있었다. 따라서, 본 발명의 화합물은 류마티스 관절염, 동맥경화증, 다발성경화증, 천식 및 기타 CCR2에 관련된 여러 질환을 치료, 예방 또는 개선하는 데 유용하게 사용될 수 있다.The compound of the present invention having the formula (1) has a high affinity for the CCR2 receptor protein, and has been shown to effectively inhibit calcium influx and chemotaxis even in a low concentration range. In addition, the inhibitory effect on CYP450 was relatively low, and it was confirmed that the compound is a safe compound having little cardiac toxicity and cytotoxicity. Thus, the compounds of the present invention can be usefully used to treat, prevent or ameliorate various diseases related to rheumatoid arthritis, arteriosclerosis, multiple sclerosis, asthma and other CCR2.
이하, 본 발명의 바람직한 실시예에 대하여 상세히 설명한다. 또한, 하기의 설명에서는 구체적인 구성요소 등과 같은 많은 특정사항들이 설명되어 있는데, 이는 본 발명의 보다 전반적인 이해를 돕기 위해서 제공된 것일 뿐 이러한 특정 사항들 없이도 본 발명이 실시될 수 있음은 이 기술분야에서 통상의 지식을 가진 자에게는 자명하다 할 것이다. 그리고, 본 발명을 설명함에 있어서, 관련된 공지 기능 혹은 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다.Hereinafter, preferred embodiments of the present invention will be described in detail. In addition, many specific details such as specific components are described in the following description, which is provided to help a more general understanding of the present invention, and it is common in the art that the present invention may be practiced without these specific details. It is self-evident to those who have knowledge of the world. In describing the present invention, when it is determined that a detailed description of a related known function or configuration may unnecessarily obscure the subject matter of the present invention, the detailed description thereof will be omitted.
본 발명은 CCR2 길항 효과를 나타내는 화학식 1의 화합물, 또는 이것의 이성질체 및 약학적으로 허용 가능한 염을 제공한다.The present invention provides compounds of formula (1), or isomers and pharmaceutically acceptable salts thereof, which exhibit CCR2 antagonistic effects.
[화학식 1][Formula 1]
Figure PCTKR2010003790-appb-I000001
Figure PCTKR2010003790-appb-I000001
상기 화학식 1에서,In Chemical Formula 1,
R1는 독립적으로 수소 원자, C1 - C3 알킬, 페닐, 벤질, 벤조일, 벤젠술포닐, C1 - C3 알킬카르보닐, C3 - C7 시클로알킬, R 1 is independently a hydrogen atom, C 1 -C 3 alkyl, phenyl, benzyl, benzoyl, benzenesulfonyl, C 1 -C 3 alkylcarbonyl, C 3 -C 7 cycloalkyl,
[화학식 2][Formula 2]
Figure PCTKR2010003790-appb-I000002
Figure PCTKR2010003790-appb-I000002
[화학식 3][Formula 3]
Figure PCTKR2010003790-appb-I000003
, 및
Figure PCTKR2010003790-appb-I000003
, And
[화학식 4][Formula 4]
Figure PCTKR2010003790-appb-I000004
Figure PCTKR2010003790-appb-I000004
로 이루어진 군에서 선택될 수 있고; It may be selected from the group consisting of;
R10, R11 및 R12는 독립적으로 수소 원자, C1 - C3 알킬, 페닐, 및 벤질기로 이루어진 군에서 선택될 수 있고; R 10 , R 11 and R 12 can be independently selected from the group consisting of hydrogen atom, C 1 -C 3 alkyl, phenyl, and benzyl group;
R1의 일부로서 포함되는 모든 벤젠기는 독립적으로 C1 - C3 알킬, C1 - C2 할로알킬, 할로겐 원자, 및 시아노기로 이루어진 군에서 선택되는 복수의 치환체를 가질 수 있고; All benzene groups included as part of R 1 may independently have a plurality of substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, a halogen atom, and a cyano group;
R2, R3, R4, R5, R6, R7, R8 및 R9는 독립적으로 수소 원자, 및 C1 - C3 알킬 중에서 선택될 수 있고; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 can be independently selected from a hydrogen atom and C 1 -C 3 alkyl;
R6과 R7, R8과 R9는 독립적으로 카르보닐기로 선택될 수 있고; R 6 and R 7 , R 8 and R 9 can be independently selected from a carbonyl group;
상기 할로겐이란 불소, 염소 및 브롬 원자로 이루어진 군에서 선택됨.The halogen is selected from the group consisting of fluorine, chlorine and bromine atoms.
본 발명은 MCP-1 및 CCR2 수용체의 상호작용을 길항함으로서 항염증 및 면역기능 조절을 통해 CCR2와 관련된 여러 질환에 대하여 치료 효과를 나타내는 상기 화학식 1의 화합물에 관한 것으로서, 이 화합물의 약학적으로 허용 가능한 염, 기하 또는 광학 이성질체, 수화물, 용매화물 또는 결정다형체를 포함한다.The present invention relates to a compound of Chemical Formula 1, which exhibits a therapeutic effect against various diseases related to CCR2 through antagonizing the interaction of MCP-1 and CCR2 receptors, thereby controlling anti-inflammatory and immune function. Possible salts, geometric or optical isomers, hydrates, solvates or polymorphs.
약학적으로 허용 가능한 염이란, 본 발명에서 제시된 화합물의 특정 관능기에 따라 통상의 유기합성 방법에 의해 제조 가능한 산 부가염 또는 염기 부가염을 의미한다. 이때 부가되는 산 또는 염기는 인체에 무해하거나 비교적 독성이 적어서 약물의 제조에 사용될 수 있는 것이다. 본 발명의 화합물이 염기성일 경우 염이 형성되기 위해서는 적절한 양의 산이 부가되어야 한다. 이때 바람직한 산 부가염은 염산, 브롬산, 질산, 황산, 요오드산 등의 무기산과, 아세트산, 시트르산, 푸마르산, 갈락탐산, 말론산, 말레산, 숙신산, 타르타르산, 메탄술폰산, 젖산, 옥살산, 프로피온산, 살리실산, 만델산, 프탈산 등의 유기산을 포함한다. 또한 본 발명의 화합물이 산성일 경우 염이 형성되기 위해서는 적절한 양의 염기가 부가되어야 한다. 이때 바람직한 염기 부가염은 암모늄, 나트륨, 칼륨, 칼슘, 마그네슘, 유기암모늄 등을 포함한다. Pharmaceutically acceptable salts refer to acid addition salts or base addition salts which can be prepared by conventional organic synthesis methods depending on the specific functional groups of the compounds presented herein. At this time, the added acid or base is harmless to the human body or relatively less toxic and can be used in the manufacture of a drug. If the compounds of the present invention are basic, an appropriate amount of acid must be added for the salt to form. Preferred acid addition salts include inorganic acids such as hydrochloric acid, bromic acid, nitric acid, sulfuric acid and iodic acid, acetic acid, citric acid, fumaric acid, galactamic acid, malonic acid, maleic acid, succinic acid, tartaric acid, methanesulfonic acid, lactic acid, oxalic acid and propionic acid. Organic acids such as salicylic acid, mandelic acid, and phthalic acid. In addition, when the compound of the present invention is acidic, an appropriate amount of base must be added to form a salt. Preferred base addition salts here include ammonium, sodium, potassium, calcium, magnesium, organoammonium and the like.
한편 본 발명에서 제시된 화합물은 용매화되지 않거나 또는 물을 포함한 수화물 또는 통상의 유기합성 과정에서 사용되는 유기용매를 포함한 용매화물이 될 수 있으며, 이러한 무수물, 수화물 또는 용매화물은 모두 본 발명의 범위에 속하는 것으로 본다.Meanwhile, the compounds presented in the present invention may be unsolvated or hydrates containing water or solvates including organic solvents used in a conventional organic synthesis process, and all of these anhydrides, hydrates or solvates are within the scope of the present invention. Seen to belong.
한편 본 발명에서 제시된 화합물은 고체 상태로 존재하는 방식으로서 무정형 또는 다수의 결정다형(polymorphism)을 나타낼 수 있으며, 이러한 무정형 또는 각각의 결정다형은 모두 본 발명의 범위에 속하는 것으로 본다.Meanwhile, the compounds presented in the present invention may exhibit amorphous or multiple polymorphisms in a solid state, and all of these amorphous or respective polymorphisms are considered to be within the scope of the present invention.
본 발명의 화합물들은 통상적인 유기합성 기술에 의해 다수의 방법으로 제조될 수 있다. 또한 본 발명의 화합물들에 공통적으로 포함되는 3-아미노피롤리딘 구조는 상업적으로 이용 가능한 원료에 따라 다수의 방법으로 도입될 수 있다. 구체적으로는 하기 반응식 1 내지 6에 제시된 방법에 따라 본 발명의 화합물을 합성할 수 있다.The compounds of the present invention can be prepared in a number of ways by conventional organic synthesis techniques. In addition, the 3-aminopyrrolidine structure commonly included in the compounds of the present invention can be introduced in a number of ways, depending on commercially available raw materials. Specifically, the compounds of the present invention can be synthesized according to the methods shown in Schemes 1 to 6 below.
하기 반응식 1에 따르면, 본 발명의 화합물의 제조를 위한 공통적인 중간체 화합물의 제조 방법을 제시한다. 3-아미노피롤리딘 구조를 도입하기 위해 사용되는 원료는 화합물 (3)과 같은 (3R)-(-)-1-벤질-3-아미노피롤리딘이다. 이때 피롤리딘 고리의 3번 탄소는 키랄성을 나타내는데, 본 발명에서 제시되는 3-아미노피롤리딘 구조를 포함하는 모든 화합물은 화합물 (3)의 명명법을 기준으로 하여 (R)-형태에 한정된다.According to Scheme 1 below, a process for the preparation of common intermediate compounds for the preparation of the compounds of the present invention is presented. The raw material used to introduce the 3-aminopyrrolidine structure is (3R)-(-)-1-benzyl-3-aminopyrrolidine such as compound (3). Wherein carbon 3 of the pyrrolidine ring exhibits chirality, and all compounds comprising the 3-aminopyrrolidine structure presented in the present invention are limited to the (R) -form based on the nomenclature of compound (3) .
[반응식 1]Scheme 1
Figure PCTKR2010003790-appb-I000005
Figure PCTKR2010003790-appb-I000005
상기 반응식 1에 의하면, 상업적으로 이용 가능한 출발물질인 화합물 (1)을 아미노산의 한 종류인 글리신과 함께 염기성 및 수성 조건에서 반응시켜 화합물 (2)를 합성할 수 있다. 상기 기술된 키랄성 3-아미노피롤리딘의 유도체인 화합물 (3)을 화합물 (2)와 반응시켜 아미드 결합을 형성시키는 방법은 다수의 공지 방법에 따라 이루어질 수 있다. 본 명세서에서는 화합물 (2)의 카르복실산을 활성화시키는 방법으로서 이소부틸 클로로포르메이트 (isobutyl chloroformate)를 예시하였으며, 이때 염기는 N-메틸모폴린(N-methylmorpholine ; NMM)을 사용하여 화합물 (4)를 용이하게 제조할 수 있다. 화합물 (4)의 N-벤질기는 보호기의 의미로서, 피롤리딘 구조에 N-알킬화 및 기타 N-치환체를 제조하기 위해서는 벤질기를 탈보호하여야 한다. 이를 위한 통상적인 방법으로서 팔라듐 촉매(Pd(OH)2)하에 수소 가스를 사용하여 용이하게 화합물 (5)를 제조할 수 있다. 이렇게 제조된 화합물 (5)는 본 발명에서 제시된 CCR2 길항 효과를 나타내는 다양한 구조의 화합물을 제조하기 위한 주요 중간체로 활용될 수 있다.According to Scheme 1, Compound (2) can be synthesized by reacting Compound (1), which is a commercially available starting material, with basic glycine, an amino acid, under basic and aqueous conditions. The method of reacting compound (3), which is a derivative of the chiral 3-aminopyrrolidine described above with compound (2), to form an amide bond can be made according to a number of known methods. In this specification, isobutyl chloroformate is exemplified as a method of activating the carboxylic acid of compound (2), wherein the base is N-methylmorpholine (NMM). ) Can be easily produced. The N-benzyl group of compound (4) means a protecting group, which must deprotect the benzyl group in order to prepare N-alkylation and other N-substituents in the pyrrolidine structure. As a conventional method for this, compound (5) can be easily prepared using hydrogen gas under a palladium catalyst (Pd (OH) 2 ). Compound (5) thus prepared can be utilized as a major intermediate for preparing compounds of various structures exhibiting the CCR2 antagonistic effect presented in the present invention.
한편 반응식 1에서 기술된 방법에 따라 제조되는 모든 중간체 화합물은 고체 상태로 수득할 수 있으며, 구체적으로는 비극성 용매하에서 목적하는 화합물을 고체화시키는 것으로서, 본 발명에서는 공업적 대량 생산에 용이한 제조 방법을 제공한다.On the other hand, all intermediate compounds prepared according to the method described in Scheme 1 can be obtained in the solid state, specifically solidifying the desired compound in a non-polar solvent, the present invention provides a manufacturing method that is easy for industrial mass production to provide.
본 발명에서 제시된 CCR2 길항제로서의 화합물 (9)의 합성은 하기 반응식 2에 따라 이루어질 수 있다.Synthesis of compound (9) as a CCR2 antagonist presented in the present invention can be made according to Scheme 2 below.
[반응식 2]Scheme 2
Figure PCTKR2010003790-appb-I000006
Figure PCTKR2010003790-appb-I000006
상기 반응식 1의 방법에 따라 제조된 화합물 (5)를 출발물질로 하여, t-부톡시카르보닐기(Boc)로 보호화되고 R2, R3, R4, R5, R6, R7, R8 및 R9가 치환된 피페라지닐에탄메실레이트 (6)과 염기성 조건에서 반응시켜 중간체 화합물 (7)을 수득한다. 이때 R2, R3, R4, R5, R6, R7, R8 및 R9는 본 명세서에 정의된 바와 같다. 중간체 (7)을 염산이 포화된 에탄올에서 탈보호화 반응을 시켜 피페라진 중간체 (8)을 염산염 형태로 수득한다. 이 화합물을 염기성 조건에서 다양한 시약과 반응시켜 본 발명에서 목적하는 CCR2 길항제로서의 화합물 (9)를 제조할 수 있다.Using compound (5) prepared according to the method of Scheme 1 as a starting material, protected with t-butoxycarbonyl group (Boc) and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are reacted with substituted piperazinylethane mesylate (6) under basic conditions to give an intermediate compound (7). Wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined herein. The intermediate (7) is subjected to deprotection reaction in ethanol saturated with hydrochloric acid to obtain the piperazine intermediate (8) in hydrochloride form. This compound can be reacted with various reagents under basic conditions to prepare compound (9) as the CCR2 antagonist desired in the present invention.
[반응식 3]Scheme 3
Figure PCTKR2010003790-appb-I000007
Figure PCTKR2010003790-appb-I000007
본 발명에서 제시하는 CCR2 길항제로서의 화합물 (9)를 제조하기 위하여 반응식 3의 방법을 이용할 수도 있다. 상기 반응식 1의 방법에 따라 제조된 화합물 (5)를 출발물질로 하여, R6, R7, R8 및 R9가 치환된 에폭시 화합물 또는 클로로에탄올 유도체를 이용하여 염기성 조건하에 반응시켜 중간체 화합물 (10)을 제조한다. 이때 R6, R7, R8 및 R9는 본 명세서에 정의된 바와 같다.The method of Scheme 3 can also be used to prepare compound (9) as a CCR2 antagonist presented in the present invention. Using compound (5) prepared according to the method of Scheme 1 as a starting material, an intermediate compound was reacted under basic conditions using an epoxy compound or chloroethanol derivative substituted with R 6 , R 7 , R 8 and R 9. 10) to manufacture. Wherein R 6 , R 7 , R 8 and R 9 are as defined herein.
에탄올 유도체 (10)으로부터 염기성 조건에서 메실 클로라이드(methanesulfonyl chloride ; MsCl)와 반응시켜 중간체 화합물 (11)을 수득할 수 있는데, 화합물 (11)은 필요에 따라 정제, 분리하거나 또는 정제하지 않고 다음 반응을 진행할 수 있다. 본 발명에서 목적하는 화합물 (9)를 제조하기 위하여 중간체 (11)을 염기성 조건하에 R1, R2, R3, R4 및 R5가 치환된 피페라진 유도체 (12)와 반응시킨다. 이때 사용되는 피페라진 유도체 (12)는 필요에 따라 염산염의 형태를 취할 수 있으며, R1, R2, R3, R4 및 R5는 본 명세서에 정의된 바와 같다.Intermediate compound (11) can be obtained from the ethanol derivative (10) by reacting with methanesulfonyl chloride (MSCl) under basic conditions, whereby the compound (11) is purified, separated or not purified as necessary, and the following reaction is carried out. You can proceed. In order to prepare the desired compound (9) in the present invention, the intermediate (11) is reacted with a piperazine derivative (12) in which R 1 , R 2 , R 3 , R 4 and R 5 are substituted under basic conditions. The piperazine derivative (12) used at this time may take the form of a hydrochloride salt as needed, and R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein.
본 발명에서 제시된 CCR2 길항제로서의 화합물 (9)의 또 다른 제조 방법은 하기 반응식 4에서 기술된 바와 같다.Another method for preparing compound (9) as a CCR2 antagonist presented herein is as described in Scheme 4 below.
[반응식 4]Scheme 4
Figure PCTKR2010003790-appb-I000008
Figure PCTKR2010003790-appb-I000008
피페라진 유도체 (12)를 출발물질로 하여, R6, R7, R8 및 R9가 치환된 에폭시 화합물 또는 클로로에탄올 유도체를 이용하여 염기성 조건하에 반응시켜 중간체 화합물 (13)을 제조한다. 이때 R1, R2, R3, R4, R5, R6, R7, R8 및 R9는 본 명세서에 정의된 바와 같다. 에탄올 유도체 (13)로부터 염기성 조건에서 메실 클로라이드와 반응시켜 중간체 화합물 (14)를 수득할 수 있는데, 화합물 (14)는 필요에 따라 정제, 분리하거나 또는 정제하지 않고 다음 반응을 진행할 수 있다. 본 발명에서 목적하는 화합물 (9)를 제조하기 위하여 중간체 (14)를 염기성 조건하에 피롤리딘 중간체 (5)와 반응시킨다.Using the piperazine derivative (12) as a starting material, an intermediate compound (13) is prepared by reacting under basic conditions using an epoxy compound or a chloroethanol derivative substituted with R 6 , R 7 , R 8 and R 9 . Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are as defined herein. Intermediate compound (14) can be obtained by reacting with mesyl chloride under basic conditions from ethanol derivative (13), which compound (14) can be subjected to the next reaction without purification, separation or purification as necessary. Intermediate (14) is reacted with pyrrolidine intermediate (5) under basic conditions to produce compound (9) desired in the present invention.
본 발명에서 제시된 CCR2 길항제로서의 화합물 (9)의 또 다른 제조 방법은 하기 반응식 5에서 기술된 바와 같다.Another method for preparing compound (9) as a CCR2 antagonist presented herein is as described in Scheme 5 below.
[반응식 5]Scheme 5
Figure PCTKR2010003790-appb-I000009
Figure PCTKR2010003790-appb-I000009
피페라진 유도체 (12)를 출발물질로 하여, R6, R7 및 R8이 치환된 2-클로로케톤 유도체를 이용하여 염기성 조건하에 중간체 화합물 (15)를 제조한다. 이때 R1, R2, R3, R4, R5, R6, R7 및 R8은 본 명세서에 정의된 바와 같다. 중간체 화합물 (15)는 피롤리딘 중간체 (5)와 함께 환원성 아민화 반응시켜 목적 화합물 (9)를 제조할 수 있다. 이때 사용하는 환원제는 다수의 공지 방법에 따라 다양하게 선택될 수 있으나, 본 명세서에서는 비교적 환원성이 약한 환원제인 나트륨 트리아세톡시보로히드라이드 (sodium triacetoxyborohydride ; NaBH(OAc)3)를 사용하여 N-알킬피롤리딘 화합물의 용이한 제조법을 예시한다.Using the piperazine derivative (12) as a starting material, an intermediate compound (15) is prepared under basic conditions using a 2-chloroketone derivative substituted with R 6 , R 7 and R 8 . Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein. The intermediate compound (15) can be subjected to reductive amination reaction with the pyrrolidine intermediate (5) to produce the target compound (9). At this time, the reducing agent used may be variously selected according to a number of known methods, but in the present specification, N-alkyl using sodium triacetoxyborohydride (NaBH (OAc) 3 ), which is a relatively low reducing agent, is used. The easy preparation of a pyrrolidine compound is illustrated.
한편 본 명세서에서 정의된 화학식 1의 R6과 R7, R8과 R9는 독립적으로 카르보닐기를 포함하며, CCR2 길항제로서의 이러한 화합물 (20)은 하기 반응식 6에 예시된 방법에 따라 제조될 수 있다.Meanwhile R 6 and R 7 , R 8 and R 9 of Formula 1 as defined herein independently include a carbonyl group, and such a compound (20) as a CCR2 antagonist may be prepared according to the method illustrated in Scheme 6 below. .
[반응식 6]Scheme 6
Figure PCTKR2010003790-appb-I000010
Figure PCTKR2010003790-appb-I000010
상기 방법에 의하면, t-부톡시카르보닐기(Boc)로 보호화되고 R2, R3, R4 및 R5가 치환된 피페라진 (16)을 출발물질로 하여 염기성 조건하에 R8 및 R9가 치환된 2-클로로아세틸 클로라이드 유도체와 반응시켜 화합물 (17)을 제조한다. 이때 R2, R3, R4, R5, R8 및 R9은 본 명세서에 정의된 바와 같다. 화합물 (17)로부터 중간체 (5)와 염기성 조건하에 치환 반응을 거쳐 화합물 (18)을 제조할 수 있으며, 적절한 용매하에 산성 조건에서 보호기를 제거하여 화합물 (19)를 수득한다. 중간체 화합물 (19)로부터 다양한 할로겐 시약을 사용하여 본 발명에서 제시하는 CCR2 길항제로서의 화합물 (20)을 제조할 수 있다.According to this method, R 8 and R 9 are formed under basic conditions, starting with piperazine (16) protected with a t-butoxycarbonyl group (Boc) and substituted with R 2 , R 3 , R 4 and R 5 . Compound (17) is prepared by reaction with a substituted 2-chloroacetyl chloride derivative. Wherein R 2 , R 3 , R 4 , R 5 , R 8 and R 9 are as defined herein. Compound (18) can be prepared from compound (17) via an intermediate reaction with intermediate (5) under basic conditions, and the protecting group is removed under acidic conditions under a suitable solvent to give compound (19). Various halogen reagents can be prepared from intermediate compound (19) to prepare compound (20) as a CCR2 antagonist set forth in the present invention.
상기 반응식 1 내지 6에 제시된 방법에 따라 본 발명에서 제시하는 CCR2 길항제로서의 화합물은 구체적으로 다음과 같다.Compounds as CCR2 antagonists according to the present invention according to the methods shown in Schemes 1 to 6 are as follows.
실시예 화학명 Example Chemical Name
1 N-{[1-(2-(1-(페닐아미노카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-일-1 N-{[1- (2- (1- (phenylaminocarbonyl) -piperazin-4-yl) ethyl) -pyrrolidin- (3R) -yl-
카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 Carbamoyl] -methyl} -3-trifluoromethylbenzamide
2 N-{[1-(2-(1-(p-톨릴아미노카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-2 N-{[1- (2- (1- (p-tolylaminocarbonyl) -piperazin-4-yl) ethyl) -pyrrolidine- (3R)-
일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide
3 N-{[1-(2-(1-(4-클로로페닐아미노카르보닐)-피페라진-4-일)에틸)-피롤리딘3 N-{[1- (2- (1- (4-chlorophenylaminocarbonyl) -piperazin-4-yl) ethyl) -pyrrolidine
-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 -(3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide
4 N-{[1-(2-(1-(메톡시카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-일-카바4 N-{[1- (2- (1- (methoxycarbonyl) -piperazin-4-yl) ethyl) -pyrrolidin- (3R) -yl-carba
모일]-메틸}-3-트리플루오로메틸벤즈아미드 Moyl] -methyl} -3-trifluoromethylbenzamide
5 N-{[1-(2-(1-(에톡시카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-일-카바5 N-{[1- (2- (1- (ethoxycarbonyl) -piperazin-4-yl) ethyl) -pyrrolidin- (3R) -yl-carba
모일]-메틸}-3-트리플루오로메틸벤즈아미드 Moyl] -methyl} -3-trifluoromethylbenzamide
6 N-{[1-(2-(4-벤조일피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}6 N-{[1- (2- (4-benzoylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl}
-3-트리플루오로메틸벤즈아미드 -3-trifluoromethylbenzamide
7 N-{[1-(2-(4-(2-메틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모7 N-{[1- (2- (4- (2-methylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamo
일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl] -methyl} -3-trifluoromethylbenzamide
8 N-{[1-(2-(4-(3-메틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모8 N-{[1- (2- (4- (3-methylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamo
일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl] -methyl} -3-trifluoromethylbenzamide
9 N-{[1-(2-(4-(4-메틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모9 N-{[1- (2- (4- (4-methylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamo
일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl] -methyl} -3-trifluoromethylbenzamide
10 N-{[1-(2-(4-(4-플루오로벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바10 N-{[1- (2- (4- (4-fluorobenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carba
모일]-메틸}-3-트리플루오로메틸벤즈아미드 Moyl] -methyl} -3-trifluoromethylbenzamide
11 N-{[1-(2-(4-(4-시아노벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모11 N-{[1- (2- (4- (4-cyanobenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamo
일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl] -methyl} -3-trifluoromethylbenzamide
12 N-{[1-(2-(4-(4-에틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모12 N-{[1- (2- (4- (4-ethylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamo
일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl] -methyl} -3-trifluoromethylbenzamide
13 N-{[1-(2-(4-(페닐술포닐)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-13 N-{[1- (2- (4- (phenylsulfonyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl]-
메틸}-3-트리플루오로메틸벤즈아미드 Methyl} -3-trifluoromethylbenzamide
14 N-{[1-(2-(4-프로피오닐피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메14 N-{[1- (2- (4-propionylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -meth
틸}-3-트리플루오로메틸벤즈아미드 Tyl} -3-trifluoromethylbenzamide
15 N-{[1-(2-(4-벤질피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-15 N-{[1- (2- (4-benzylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-
트리플루오로메틸벤즈아미드 Trifluoromethylbenzamide
16 N-{[1-(1-(4-벤조일피페라진-1-일)프로판-2-일)-피롤리딘-(3R)-일-카바모16 N-{[1- (1- (4-benzoylpiperazin-1-yl) propan-2-yl) -pyrrolidin- (3R) -yl-carbamo
일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl] -methyl} -3-trifluoromethylbenzamide
17 N-{[1-(3-(4-벤조일피페라진-1-일)부탄-2-일)-피롤리딘-(3R)-일-카바모일]-17 N-{[1- (3- (4-benzoylpiperazin-1-yl) butan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl]-
메틸}-3-트리플루오로메틸벤즈아미드 Methyl} -3-trifluoromethylbenzamide
18 N-{[1-(2-(4-벤조일피페라진-1-일)프로판-1-일)-피롤리딘-(3R)-일-카바모18 N-{[1- (2- (4-benzoylpiperazin-1-yl) propan-1-yl) -pyrrolidin- (3R) -yl-carbamo
일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl] -methyl} -3-trifluoromethylbenzamide
19 N-{[1-(1-(4-벤조일피페라진-1-일)부탄-2-일)-피롤리딘-(3R)-일-카바모일]-19 N-{[1- (1- (4-benzoylpiperazin-1-yl) butan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl]-
메틸}-3-트리플루오로메틸벤즈아미드 Methyl} -3-trifluoromethylbenzamide
20 N-{[1-(2-(4-벤조일피페라진-1-일)부틸)-피롤리딘-(3R)-일-카바모일]-메20 N-{[1- (2- (4-benzoylpiperazin-1-yl) butyl) -pyrrolidin- (3R) -yl-carbamoyl] -meth
틸}-3-트리플루오로메틸벤즈아미드 Tyl} -3-trifluoromethylbenzamide
21 N-{[1-(2-(4-벤조일피페라진-1-일)-2-메틸프로필)-피롤리딘-(3R)-일-카바모21 N-{[1- (2- (4-benzoylpiperazin-1-yl) -2-methylpropyl) -pyrrolidin- (3R) -yl-carbamo
일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl] -methyl} -3-trifluoromethylbenzamide
22 N-{[1-(1-(4-벤조일피페라진-1-일)-2-메틸프로판-2-일)-피롤리딘-(3R)-일-카22 N-{[1- (1- (4-benzoylpiperazin-1-yl) -2-methylpropan-2-yl) -pyrrolidin- (3R) -yl-ka
바모일]-메틸}-3-트리플루오로메틸벤즈아미드 Barmoyl] -methyl} -3-trifluoromethylbenzamide
23 N-{[1-(3-(4-(3-클로로페닐)피페라진-1-일)부탄-2-일)-피롤리딘-(3R)-일-카23 N-{[1- (3- (4- (3-chlorophenyl) piperazin-1-yl) butan-2-yl) -pyrrolidin- (3R) -yl-ka
바모일]-메틸}-3-트리플루오로메틸벤즈아미드 Barmoyl] -methyl} -3-trifluoromethylbenzamide
24 N-{[1-(1-(4-페닐피페라진-1-일)프로판-2-일)-피롤리딘-(3R)-일-카바모일]-24 N-{[1- (1- (4- (phenylphenylazin-1-yl) propan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl]-
메틸}-3-트리플루오로메틸벤즈아미드 Methyl} -3-trifluoromethylbenzamide
25 N-{[1-(1-(4-시클로헥실피페라진-1-일)프로판-2-일)-피롤리딘(3R)-일-카바모25 N-{[1- (1- (4-cyclohexylpiperazin-1-yl) propan-2-yl) -pyrrolidin (3R) -yl-carbamo
일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl] -methyl} -3-trifluoromethylbenzamide
26 N-{[1-(2-(4-(2-히드록시부틸)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모26 N-{[1- (2- (4- (2-hydroxybutyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamo
일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl] -methyl} -3-trifluoromethylbenzamide
27 N-{[1-(2-(4-(2-히드록시-2-메틸프로필)피페라진-1-일)에틸)-피롤리딘-(3R)-27 N-{[1- (2- (4- (2-hydroxy-2-methylpropyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R)-
일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide
28 N-{[1-(2-(4-(2-히드록시-2-페닐에틸)피페라진-1-일)에틸)-피롤리딘-(3R)-일28 N-{[1- (2- (4- (2-hydroxy-2-phenylethyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl
-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 -Carbamoyl] -methyl} -3-trifluoromethylbenzamide
29 N-{[1-(2-(4-(2-(4-클로로페닐)-2-히드록시에틸)피페라진-1-일)에틸)-피롤리29 N-{[1- (2- (4- (2- (4-chlorophenyl) -2-hydroxyethyl) piperazin-1-yl) ethyl) -pyrroli
딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 Din- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide
30 N-{[1-(2-(4-벤조일피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모30 N-{[1- (2- (4-benzoylpiperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamo
일]-메틸}-3-트리플루오로메틸벤즈아미드 Yl] -methyl} -3-trifluoromethylbenzamide
31 N-{[1-(2-(4-(4-메틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-31 N-{[1- (2- (4- (4-methylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-
카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 Carbamoyl] -methyl} -3-trifluoromethylbenzamide
32 N-{[1-(2-(4-(4-에틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-32 N-{[1- (2- (4- (4-ethylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-
카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 Carbamoyl] -methyl} -3-trifluoromethylbenzamide
33 N-{[1-(2-(4-(3-메틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-33 N-{[1- (2- (4- (3-methylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-
카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 Carbamoyl] -methyl} -3-trifluoromethylbenzamide
34 N-{[1-(2-(4-(2-메틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-34 N-{[1- (2- (4- (2-methylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-
카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 Carbamoyl] -methyl} -3-trifluoromethylbenzamide
35 N-{[1-(2-(4-페닐피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-35 N-{[1- (2- (4-phenylpiperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl]-
메틸}-3-트리플루오로메틸벤즈아미드 Methyl} -3-trifluoromethylbenzamide
36 N-{[1-(2-(4-(벤족시카르보닐)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일36 N-{[1- (2- (4- (benzoxycarbonyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl
-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 -Carbamoyl] -methyl} -3-trifluoromethylbenzamide
37 N-{[1-(2-(4-벤조일-2,5-디메틸피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바37 N-{[1- (2- (4-benzoyl-2,5-dimethylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carba
모일]-메틸}-3-트리플루오로메틸벤즈아미드 Moyl] -methyl} -3-trifluoromethylbenzamide
[약학적 용도][Pharmaceutical use]
본 발명의 화합물은 CCR2 수용체의 기능을 억제함으로써 다수의 질환 및 증상을 치료할 수 있다. 보다 구체적으로는, CCR2가 매개하는 염증성 질환, 장애 및 증상을 예방, 치료 및 개선하는데 사용하기 위한 것이다. 다른 측면에서는, MCP-1의 발현 또는 과다 발현과 관련된 질환 및 증상에 대하여 이로 인한 CCR2의 활성화를 억제 또는 조절하기 위한 것이다.The compounds of the present invention can treat a number of diseases and symptoms by inhibiting the function of the CCR2 receptor. More specifically, for use in preventing, treating and ameliorating inflammatory diseases, disorders and symptoms mediated by CCR2. In another aspect, to inhibit or regulate activation of CCR2 thereby for diseases and symptoms associated with or overexpression of MCP-1.
이와 관련된 질환은 염증 및 자가면역에 관련된 질환, 구체적으로 알레르기성 비염, 호흡기성 알레르기 질환, 만성 폐쇄성 폐질환, 천식, 폐렴, 류마티스성 관절염, 포도막염, 다발성 경화증, 접촉성 피부염, 아토피성 피부염, 크론씨병, 대장염, 신염을 포함한다. 또한 대사성 질환으로서 당뇨병, 당뇨 합병증, 비만, 고지혈증을 포함한다. 또한 혈관 관련 질환으로서 동맥경화증, 재협착증에 이용될 수 있으며 기타 혈관보호제로도 이용될 수 있다. 또한 기관 이식의 거절반응에 대한 면역억제제로서도 이용될 수 있다.Related diseases include inflammation and autoimmune diseases, specifically allergic rhinitis, respiratory allergic disease, chronic obstructive pulmonary disease, asthma, pneumonia, rheumatoid arthritis, uveitis, multiple sclerosis, contact dermatitis, atopic dermatitis, Crohn's disease Contains colitis, nephritis. Metabolic diseases also include diabetes, diabetes complications, obesity, hyperlipidemia. In addition, it may be used for atherosclerosis and restenosis as a blood vessel-related disease, and may also be used for other vascular protective agents. It can also be used as an immunosuppressive agent for rejection of organ transplantation.
한편 본 발명에서 제시된 화합물은 CCR2 수용체의 병리학적 역할에 기인하는 질환 및 증상에 모두 이용될 수 있다. 따라서 이러한 질환 및 증상에 대한 치료제 또는 증상 완화제로서의 용도는 여기에 기술된 것에 한정되지 않는다.On the other hand, the compounds presented in the present invention can be used for both diseases and symptoms due to the pathological role of the CCR2 receptor. Thus, the use as a therapeutic or symptomatic alleviator for such diseases and conditions is not limited to those described herein.
본 발명에서 제시된 화합물은 CCR2 길항제로서의 유효성분이며, 이 유효성분의 1일 경구투여량은 0.01mg 내지 1,000mg/kg의 범위, 바람직하게는 0.1mg 내지 100mg의 범위를 가진다. 이는 해당 질환 및 투여 대상에 따라 선택된 투여 방식에 적절한 형태로 구성된다. 즉 1일 1회 내지 5회의 투약 요법에 따라 투여될 수 있으며, 단독 또는 필요에 따라 타 약제와의 병용 투여가 가능하다.The compound presented in the present invention is an active ingredient as a CCR2 antagonist, and the daily oral dose of this active ingredient is in the range of 0.01 mg to 1,000 mg / kg, preferably in the range of 0.1 mg to 100 mg. It is configured in a form suitable for the administration mode selected according to the disease and the administration target. That is, it may be administered according to the dosage regimen once to five times per day, and may be administered alone or in combination with other drugs as necessary.
한편 본 발명은 상기 화학식 1의 화합물을 함유하는 약학적 조성물에 관한 것이다.Meanwhile, the present invention relates to a pharmaceutical composition containing the compound of Formula 1.
상기 약학적 조성물은 정제, 발포성 정제, 캅셀제, 과립제, 산제, 서방성 정제, 서방성 캅셀제 등을 포함한다. 또한 정맥 또는 근육내 주사제, 현탁액, 좌제, 피부 패취제, 복강내 주사제, 비강내 전달기구 등의 제형을 포함하며 기타 유효성분 및 투여 목적에 적합한 약학적 형태로서 투여될 수 있다.The pharmaceutical composition includes tablets, effervescent tablets, capsules, granules, powders, sustained-release tablets, sustained-release capsules and the like. It may also be administered as a pharmaceutical form, including formulations such as intravenous or intramuscular injections, suspensions, suppositories, skin patches, intraperitoneal injections, intranasal delivery devices, and the like, suitable for other active ingredients and administration purposes.
본 발명에서 제시된 화합물을 유효성분으로 한 바람직한 약학적 조성물을 제조하기 위하여, 생리학적으로 내성이 있는 부형제, 희석제, 보조제, 피복물질, 항산화제, 방향성 물질을 포함하여 제형화할 수 있다. 부형제 및 보조제의 구체적인 예는 젤라틴, 자당, 유당, 레시틴, 펙틴, 전분, 시클로덱스트린, 시클로덱스트린 유도체, 덱스트란, 폴리비닐피롤리돈, 폴리비닐 아세테이트, 아라비아 고무, 알긴산, 틸로오스, 활석, 리코포듐, 실리식산, 인산수소칼슘, 셀룰로오스, 메톡시프로필셀룰로오스, 메틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 히드록시프로필메틸셀룰로오스 프탈레이트, 포화 또는 불포화 지방산, 식물성 글리세롤 에스테르, 폴리글리세롤 에스테르, 알코올, 폴리에틸렌글리콜, 지방족 알코올, 글리콜, 글리세롤, 디에틸렌글리콜, 프로필렌글리콜, 소르비톨, 만니톨, 포화 또는 불포화 지방산의 에스테르가 있다. 또한 추가적으로 사용할 수 있는 보조제 또는 붕해제의 구체적인 예는 교차 결합된 폴리비닐피롤리돈, 카르복시메틸전분 나트륨, 카르복시메틸셀룰로오스 나트륨, 미세결정성 셀룰로오스가 있다. 또한 정제의 피복물질을 사용할 수 있는데, 이에 대한 구체적인 예는 아크릴산, 메타크릴산, 메타크릴산의 에스테르 중합체 및 공중합체, 제인, 에틸셀룰로오스, 에틸셀룰로오스 석시네이트, 셀락, 시트르산 에스테르, 타르타르 에스테르, 글리세롤, 글리세롤 에스테르, 폴리에틸렌 글리콜이 있다. 한편 바람직한 제형화 또는 현탁액의 제조를 위하여 물 또는 생리학적으로 허용되는 범위내에서 적절한 분량의 유기용매를 사용할 수 있다. 특히 액체 제형에 있어서는 보존제, 항산화제 및 방향 강화제를 사용할 수 있는데, 이에 대한 구체적인 예는 솔베이트 칼륨, 메틸 4-히드록시벤조에이트, 프로필 4-히드록시벤조에이트, 아스코빅산, 페퍼민트 오일 등이 있다. 바람직한 제형화를 위하여 필요에 따라서는 폴리비닐피롤리돈, 폴리솔베이트 80과 같은 용해제 및 에멀젼화제를 사용할 수 있다.In order to prepare a preferred pharmaceutical composition using the compound of the present invention as an active ingredient, it may be formulated to include physiologically resistant excipients, diluents, adjuvants, coating materials, antioxidants, aromatic substances. Specific examples of excipients and auxiliaries include gelatin, sucrose, lactose, lecithin, pectin, starch, cyclodextrin, cyclodextrin derivatives, dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginic acid, tylose, talc, ricoh Fordium, silicic acid, calcium hydrogen phosphate, cellulose, methoxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, saturated or unsaturated fatty acids, vegetable glycerol esters, polyglycerol esters, alcohols, polyethylene glycols, Esters of aliphatic alcohols, glycols, glycerol, diethylene glycol, propylene glycol, sorbitol, mannitol, saturated or unsaturated fatty acids. Specific examples of supplements or disintegrants that may additionally be used are cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethylcellulose, microcrystalline cellulose. It is also possible to use tablet coatings, specific examples of which are ester polymers and copolymers of acrylic acid, methacrylic acid, methacrylic acid, zein, ethylcellulose, ethylcellulose succinate, shellac, citric acid esters, tartar esters, glycerol , Glycerol esters, polyethylene glycols. On the other hand, an appropriate amount of organic solvent may be used within water or a physiologically acceptable range for the preparation of the desired formulation or suspension. Particularly in liquid formulations, preservatives, antioxidants and fragrance enhancers can be used, specific examples of which include potassium sorbate, methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate, ascorbic acid, peppermint oil, and the like. . Solvents and emulsifiers, such as polyvinylpyrrolidone, polysorbate 80, may be used as needed for preferred formulation.
본 발명에서 제시된 화합물을 인체에 투여하기 위하여, 대표적인 약학적 방법을 정제를 예시로 설명하면 구체적으로 다음과 같다. 하기 제시된 화합물 A, B 및 C는 본 발명에서 CCR2 수용체 길항을 위한 유효 성분으로 제시한 물질을 의미한다.In order to administer the compound of the present invention to the human body, a representative pharmaceutical method will be described in detail as an example. Compounds A, B and C set forth below mean substances which have been proposed as active ingredients for CCR2 receptor antagonism in the present invention.
조성물 1 (단위 : 정제당 mg)Composition 1 (unit: mg per tablet)
화합물 A : 100.00Compound A: 100.00
락토오스 : 183.00Lactose: 183.00
나트륨 라우릴술페이트(SLS) : 18.00Sodium Lauryl Sulfate (SLS): 18.00
폴리비닐 피롤리돈(PVP) : 15.00Polyvinyl Pyrrolidone (PVP): 15.00
나트륨 크로스카르멜로스 : 18.00Sodium croscarmellose: 18.00
미세결정성 셀룰로오스 : 60.00Microcrystalline Cellulose: 60.00
스테아르산 마그네슘 : 6.00Magnesium Stearate: 6.00
총량 : 400.00Total Quantity: 400.00
조성물 2 (단위 : 정제당 mg)Composition 2 (unit: mg per tablet)
화합물 B : 200.00Compound B: 200.00
락토오스 : 203.75Lactose: 203.75
나트륨 라우릴술페이트(SLS) : 15.00Sodium Lauryl Sulfate (SLS): 15.00
폴리비닐 피롤리돈(PVP) : 12.50Polyvinyl Pyrrolidone (PVP): 12.50
나트륨 크로스카르멜로스 : 15.00Sodium croscarmellose: 15.00
미세결정성 셀룰로오스 : 50.00Microcrystalline Cellulose: 50.00
스테아르산 마그네슘 : 3.75Magnesium Stearate: 3.75
총량 : 500.00Total Quantity: 500.00
조성물 3 (단위 : 정제당 mg)Composition 3 (unit: mg per tablet)
화합물 C : 100.00Compound C: 100.00
락토오스 : 213.00Lactose: 213.00
나트륨 라우릴술페이트(SLS) : 12.00Sodium Lauryl Sulfate (SLS): 12.00
폴리비닐 피롤리돈(PVP) : 10.00Polyvinyl Pyrrolidone (PVP): 10.00
나트륨 크로스카르멜로스 : 12.00Sodium croscarmellose: 12.00
미세결정성 셀룰로오스 : 50.00Microcrystalline Cellulose: 50.00
스테아르산 마그네슘 : 3.00Magnesium Stearate: 3.00
총량 : 400.00Total Quantity: 400.00
[약리학적 효과]Pharmacological effect
본 발명에서 제시된 화합물의 CCR2 길항 효과는 적절한 약리 시험에 의해 검증될 수 있다. 구체적으로는 본 발명의 화합물과 CCR2 수용체 단백질과의 친화력, 또는 세포 단위의 시험으로서 본 발명의 화합물에 의한 면역세포의 화학 주성(chemotaxis) 억제 효과 및 세포질내 칼슘 이온 유입(Ca2+ flux)의 억제 효과를 정량적으로 분석하여 판단할 수 있다. 각 약리 시험에 대한 보다 구체적인 방법은 하기 기술된 바와 같다.The CCR2 antagonistic effects of the compounds presented herein can be verified by appropriate pharmacological tests. Specifically, the affinity between the compound of the present invention and the CCR2 receptor protein, or a cell-level test, shows that the chemotaxis inhibitory effect of immune cells and the calcium ion influx (Ca 2+ flux) in the cytoplasm by the compound of the present invention. The inhibitory effect can be determined by quantitative analysis. More specific methods for each pharmacological test are as described below.
1) CCR2 수용체 단백질과의 친화력 측정(CCR2 protein binding assay )1) Measurement of affinity with CCR2 receptor protein (CCR2 protein binding assay)
CCR2에 결합하여 수용체의 신호전달을 차단하는 화합물의 친화력은 CHO세포에서 발현된 인간 유전자 재조합 CCR2 수용체 (Perkinelmer, USA)와 방사능리간드 [125I]-MCP1 (Perkinelmer, USA)을 사용하여 측정한다. 수용체 결합 분석을 위해서 사용된 완충용액은 5mM MgCl2, 1mM CaCl2 및 0.5% BSA가 함유된 50mM Hepes(pH 7.4)를 사용한다. [125I]-MCP1 결합 분석시 96-웰 플레이트에 시험 약물과 CCR2 막(10μg/well), [125I]-MCP1을 가하여 최종 부피 0.25ml의 반응 혼합물을 만들고 이를 27℃에서 60분간 배양한다. 배양 후, 이노테크 하비스터(Inotech harvester, Inotech)를 이용하여 0.5% PEI에 미리 적신 Wallac filtermat A GF/C 유리섬유 필터(Wallac, Finland)를 통하여 신속히 여과하여 반응을 종결시키고 차가운 50mM Tris-HCl(pH 7.4) 완충용액으로 세척한다. 필터를 멜티렉스(MeltiLex)로 덮고, 샘플백에 봉인하여 오븐에서 건조시킨 후, 마이크로베타 플러스(MicroBeta Plus, Wallac)로 카운트한다. 화합물의 수용체 친화력은 10μM의 고농도에서 측정하고, 10μM에서 50% 이상의 억제 효과를 나타낸 친화력이 비교적 우수한 화합물에 대하여 7~8단계 농도로 각 2개의 시험관에서 2회 반복 실험하며, 이로부터 얻은 등온선을 컴퓨터에 의한 비직선형 회귀분석에 의하여 수용체 친화력(IC50)을 계산한다 (GraphPad Prism Program, San Diego, USA). 비특이적 결합측정에는 D-Trp6-LHRH (1μM)를 사용한다.The affinity of a compound that binds to CCR2 and blocks the signaling of the receptor is measured using human recombinant recombinant CCR2 receptor (Perkinelmer, USA) and radioligand [ 125 I] -MCP1 (Perkinelmer, USA) expressed in CHO cells. The buffer used for receptor binding assays uses 50 mM Hepes (pH 7.4) containing 5 mM MgCl 2 , 1 mM CaCl 2 and 0.5% BSA. In a [ 125 I] -MCP1 binding assay, test drug, CCR2 membrane (10 μg / well), and [ 125 I] -MCP1 were added to a 96-well plate to prepare a reaction mixture with a final volume of 0.25 ml and incubated at 27 ° C. for 60 minutes. . After incubation, the reaction was terminated by rapid filtration through a Wallac filtermat A GF / C glass fiber filter (Wallac, Finland), pre-soaked with 0.5% PEI using an Inotech harvester (Inotech) and cold 50 mM Tris-HCl (pH 7.4) Wash with buffer. The filter is covered with MeltiLex, sealed in a sample bag, dried in an oven and counted with MicroBeta Plus (Wallac). The receptor affinity of the compound was measured at a high concentration of 10 μM, and repeated experiments were performed twice in each of two test tubes at 7 to 8 concentrations for a compound having a relatively high affinity showing an inhibitory effect of 50% or more at 10 μM. Receptor affinity (IC 50 ) is calculated by computer nonlinear regression (GraphPad Prism Program, San Diego, USA). D-Trp6-LHRH (1 μM) is used for nonspecific binding assays.
2) CCR2의 칼슘 유입(Ca2+ flux) 억제 효과2) Inhibitory effect of CCR2 on calcium influx (Ca 2+ flux)
CCR2b 형질전환세포(HEK293/CCR2b)를 라이신이 코팅된 black-clear bottom plate에 접종(seeding)한 후 24시간 동안 순응시키고 SFM(serum free media-DMEM)으로 교체하여 일야 방치시킨다. 다음날 Flour-4(calcium dye, Molecular probe사)를 처리하여, 배양기에 50분 동안 넣어둔 후에 칼슘이 제거된 완충용액으로 씻고 화합물을 10-15분 동안 전처리 한다. 여기에 MCP-1을 가하여 나타나는 신호를 FlexStationII (Molecular device사)에서 측정한다.CCR2b transformed cells (HEK293 / CCR2b) were seeded on lysine-coated black-clear bottom plates, allowed to acclimate for 24 hours, replaced with serum free media-DMEM (SFM) and left overnight. The next day, Flour-4 (calcium dye, Molecular probe) is treated, placed in the incubator for 50 minutes, washed with calcium-free buffer solution and the compound is pretreated for 10-15 minutes. The signal resulting from the addition of MCP-1 is measured on a FlexStation II (Molecular device).
3) 화학 주성(Chemotaxis) 억제 효과3) Inhibitory effect on chemotaxis
CCR2 기능에 대한 화합물의 길항 효과는 적당한 세포를 이용하는 백혈구 화학주성 분석법으로 측정할 수 있다. 적당한 세포에는 CCR2를 발현하고 CCR2 리간드(예를 들어, MCP-1)에 의해 유도되는 화학 주성을 나타내는 세포주, 재조합 세포 또는 분리된 세포가 포함된다. Antagonistic effects of compounds on CCR2 function can be measured by leukocyte chemotaxis assays using appropriate cells. Suitable cells include cell lines, recombinant cells or isolated cells that express CCR2 and exhibit chemotaxis induced by CCR2 ligands (eg, MCP-1).
사용한 세포주는 THP-1 세포이며, THP-1 세포는 37℃, 5% CO2 인큐베이터에서 10% 소태아혈청을 보충한 RPMI-1640에서 증식시킨다. 세포 밀도는 0.5 x 106 cells/ml 사이에서 유지시킨다. MCP-1 유발 화학 주성을 96-웰 화학 주성 챔버(Neuro Probe)에 가동시키고, 재결합 hMCP-1(10ng/ml, R&D) 또는 완충액 단독 30μl를 하부 챔버에 첨가, 각종 농도의 시험 화합물과 15분간 예비 배양된 THP-1 세포(4 x 106 cells/ml) 50μl를 상부 챔버에 첨가한다. 세포는 37℃, 5% CO2 인큐베이터에서 2시간 화학 주성을 갖도록 허용된다. 2시간 배양 후, 필터의 상부로부터 이동되지 않은 세포를 면봉으로 필터를 가볍게 닦아냄으로써 제거한다. 아래쪽 챔버로 이동된 세포는 형광판 판독기(fluorescent plate reder. λ여기=480nm, λ방출=520nm)를 이용해서 측정한다. 화학 주성 반응은 MCP-1 존재하에 이동된 세포의 평균치와 케모카인 부재시의 이동된 세포의 평균치의 비인 화학 주성 지수로서 표현될 수 있다. 이하의 수학식 1을 이용해서 저해 %를 산출한다.The cell line used is THP-1 cells and THP-1 cells are grown in RPMI-1640 supplemented with 10% fetal bovine serum in a 37 ° C., 5% CO 2 incubator. Cell density is maintained between 0.5 x 10 6 cells / ml. MCP-1 induced chemotaxis was run in a 96-well chemotaxis chamber (Neuro Probe) and 30 μl of recombination hMCP-1 (10 ng / ml, R & D) or buffer alone was added to the lower chamber, for 15 minutes with various concentrations of test compound. 50 μl of pre-cultured THP-1 cells (4 × 10 6 cells / ml) are added to the upper chamber. Cells are allowed to have 2 h chemotaxis in 37 ° C., 5% CO 2 incubator. After 2 hours of incubation, the cells that did not migrate from the top of the filter are removed by gently wiping the filter with a cotton swab. Cells transferred to the lower chamber are measured using a fluorescent plate reder (λ excitation = 480 nm , λ emission = 520 nm). The chemotactic response can be expressed as a chemotaxis index, which is the ratio of the mean of cells migrated in the presence of MCP-1 and the mean of migrated cells in the absence of chemokines. % Inhibition is computed using the following formula (1).
[수학식 1][Equation 1]
저해 % = (1-((F샘플-F완충액)/(FMCP-1-F완충액))) × 100% Inhibition = (1-((F sample -F buffer ) / (F MCP-1 -F buffer ))) × 100
식 중, F샘플은 각종 농도의 시험 화합물에 의해 미리 배양되고 하부 챔버 10ng/ml MCP-1으로 이동된 세포의 형광이고; FMCP-1은 완충액-0.1% DMSO에 의해 미리 배양되고 10ng/ml로 이동된 세포의 형광이고; F완충액은 완충액-0.1% DMSO에 의해 미리 배양되어 하부 챔버의 완충액으로 자발 이동된 세포의 형광이다.Wherein the F sample is the fluorescence of the cells previously incubated with various concentrations of the test compound and transferred to the lower chamber 10 ng / ml MCP-1; F MCP-1 is the fluorescence of cells preincubated with buffer-0.1% DMSO and shifted to 10 ng / ml; F buffer is the fluorescence of cells that have been previously incubated with buffer-0.1% DMSO and spontaneously migrated to the buffer of the lower chamber.
상기 CCR2 수용체 단백질에 대한 친화력 프로토콜에 의한 시험 결과, 본 발명의 화합물은 IC50이 1nM 내지 10μM의 범위를 가진다. 또한 상기 칼슘 유입 억제 효과 및 화학 주성 억제 효과 프로토콜에 의한 시험 결과, 본 발명의 화합물은 각각의 시험에 대하여 IC50이 1nM 내지 10μM의 범위를 가진다.Tests by the affinity protocol for the CCR2 receptor protein show that the compounds of the present invention have an IC 50 in the range of 1 nM to 10 μM. In addition, as a result of the test by the calcium influx inhibition effect and chemotaxis inhibitory effect protocol, the compound of the present invention has an IC 50 range of 1 nM to 10 μM for each test.
한편 본 발명에서 제시된 화합물에 대하여, 의약품 활성성분으로서의 유효성을 적절한 약리 시험을 통해 검증할 수 있다. 구체적으로는 복수의 약물간 상호작용을 예측하기 위하여 약물 대사 효소에 대한 저해도(CYP450 inhibition)를 평가하며, 심장 독성을 예측하기 위하여 hERG K+ 이온 통로에 대한 결합력을 평가하고, 또한 기타 다수의 세포주에 대한 세포 독성 시험을 실시하여 약물로서의 독성을 사전에 예측할 수 있다.On the other hand, for the compounds presented in the present invention, the effectiveness as a pharmaceutical active ingredient can be verified through appropriate pharmacological tests. Specifically, the CYP450 inhibition is evaluated to predict the interaction between drugs, and the binding force to the hERG K + ion channel is estimated to predict cardiac toxicity. Cytotoxicity tests on cell lines can be performed to predict the toxicity as a drug in advance.
각 약리 시험에 대한 보다 구체적인 방법은 하기 기술된 바와 같다.More specific methods for each pharmacological test are as described below.
1) CYP450 저해도 평가1) Evaluation of CYP450 Inhibition
약물대사 효소인 11종의 CYP450 효소중 5종(CYP3A4, 2C9, 2C19, 2D6, 1A2)에 대한 저해도 검색(P450-GloTM, Promega사)을 분석한다. 루시페린 측정시약을 완충액에 녹이고 각각의 CYP효소의 막을 준비한다. 화합물을 4배 농도로 6.25μl 준비하고, 효소의 종류마다 적절한 기질과 효소를 섞은 반응 혼합물을 6.25μl 가하여 10분간 방치한다. 12.5μl의 CYP효소 NADPH 재생성 시약을 가하여 반응을 30분간 시킨 후 25μl의 루시페린 측정시약을 넣고 20분간 반응시켜서 형광을 Fusion α에서 측정한다.Inhibition screening (P450-GloTM, Promega) of five of 11 CYP450 enzymes (CYP3A4, 2C9, 2C19, 2D6, 1A2), which are drug metabolizing enzymes, is analyzed. Luciferin assay reagent is dissolved in buffer and a membrane of each CYP enzyme is prepared. 6.25 μl of the compound is prepared at 4 times the concentration, and 6.25 μl of the reaction mixture of the appropriate substrate and enzyme is added for each type of enzyme and left for 10 minutes. 12.5μl of CYP enzyme NADPH regeneration reagent is added to the reaction for 30 minutes, and then 25μl luciferin measuring reagent is added and reacted for 20 minutes to measure fluorescence in Fusion α.
본 발명에서 제시된 CCR2 길항제로서의 화합물들은 상기 CYP450 저해도 평가를 실시함에 있어서 상기 기술된 5종의 CYP450 효소들에 대하여 화합물의 농도 10μM에서 50% 이하의 범위에서 결합력을 나타내어 CYP450에 대한 저해도가 비교적 낮음을 알 수 있다.Compounds as CCR2 antagonists presented in the present invention showed binding ability in the range of 10 μM or less to 50% of the concentration of the compound with respect to the five CYP450 enzymes described above in performing the CYP450 inhibitory evaluation. It can be seen that low.
2) hERG K+ 심장독성 평가2) hERG K + Cardiotoxicity Assessment
약물의 hERG K+ 이온 통로(채널) 결합력을 방사성 리간드 [3H]Astemizole 치환 평가법 (hERG 결합 검색법)으로 수행한다. hERG 세포막(2.5μg/well), [3H]-Astemizole (4nM)을 포함한 완충액에 약물을 가하여 0.2ml의 반응 혼합물을 만들고 이를 상온에서 60분간 반응시킨다. 이를 하비스터(Inotech harvester)를 이용하여 0.3% 폴리에틸렌이민에 미리 적신 Filtermat-A(Wallac) 필터로 신속히 여과, 세척한 후, 필터를 멜티렉스(MeltiLex)로 덮고, 샘플백에 봉인, 건조시켜 마이크로베타 플러스(MicroBeta Plus, Wallac)로 RI 값을 측정한다. 실험에서 얻은 저해도를 비직선형 회귀분석(GraphPad Prism Program)하여 결합억제도(IC50)를 계산하고 비특이적 결합측정에는 0.1μM의 astemizole을 사용한다.The hERG K + ion channel (channel) binding capacity of the drug is performed by radioligand [ 3 H] Astemizole substitution assay (hERG binding screening). The drug is added to a buffer containing hERG cell membrane (2.5 μg / well) and [ 3 H] -Astemizole (4 nM) to make a 0.2 ml reaction mixture, which is then reacted at room temperature for 60 minutes. This was quickly filtered and washed with a Filtermat-A (Wallac) filter pre-soaked with 0.3% polyethyleneimine using an Inotech harvester, and then the filter was covered with MeltiLex, sealed in a sample bag, dried and RI value is measured by Beta Plus (MicroBeta Plus, Wallac). The inhibition obtained from the experiment was calculated by nonlinear regression analysis (GraphPad Prism Program) to calculate the binding inhibition (IC 50 ), and 0.1μM astemizole was used for nonspecific binding measurement.
본 발명에서 제시된 CCR2 길항제로서의 화합물들에 대하여 상기 hERG K+ 심장독성 평가를 실시한 결과, 화합물의 농도 10μM에서 50% 이하의 범위에서 결합력을 나타내어 심장 독성이 거의 없는 안전한 화합물임을 예상할 수 있다.As a result of performing the hERG K + cardiotoxicity evaluation of the compounds as the CCR2 antagonists presented in the present invention, it can be expected that the compound exhibits a binding force in the range of 50% or less at a concentration of 10 μM of the compound and thus is a safe compound having little cardiac toxicity.
3) 세포독성 평가 (cell viability ; cytotoxicity)3) Cell viability (cytotoxicity)
시험 화합물의 세포독성 정도를 확인하기 위하여, THP-1 세포에 대하여 MTS(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt, Promega, U.S.A) 방법을 이용한다. MTS 방법은 세포의 생활력과 증식 및 활성을 측정할 수 있는 예민한 방법으로서 살아있는 세포의 대사과정에서 미토콘드리아의 탈수소효소(dehydrogenase)가 노란색의 MTS를 불용성인 formazan으로 전환할 수 있는 능력을 이용한 방법이다. THP-1 세포는 37℃, 5% CO2 인큐베이터에서 10% 소태아혈청을 보충한 RPMI-1640에서 증식시킨다. 세포 밀도는 0.5 x 106 cells/ml 사이에서 유지시킨다. THP-1 세포를 1 x 105 cell/ml로 96-웰 플레이트에 분주하고 시험 화합물을 1, 10μM로 처리한 다음 24시간 뒤 317μg/ml의 MTS를 96-웰 플레이트에 20μl 처리한다. 1시간 뒤 ELISA reader에서 흡광 490nm에서 측정하여 세포의 활성도를 대조군에 대한 실험군의 formazan 결정의 흡광도로 아래의 수학식 2와 같이 계산한다.To determine the degree of cytotoxicity of the test compound, MTS (3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H on THP-1 cells -tetrazolium, inner salt, Promega, USA) method. The MTS method is a sensitive method that can measure the viability, proliferation and activity of the cell and utilizes the ability of mitochondrial dehydrogenase to convert yellow MTS into insoluble formazan during metabolism of living cells. THP-1 cells are grown in RPMI-1640 supplemented with 10% fetal bovine serum in 37 ° C., 5% CO 2 incubator. Cell density is maintained between 0.5 x 10 6 cells / ml. THP-1 cells are dispensed in 96-well plates at 1 × 10 5 cells / ml, the test compounds are treated with 1, 10 μM and 20 μl of 317 μg / ml of MTS is treated 24 hours later. After 1 hour, the absorbance of the ELISA reader was measured at 490 nm, and the activity of the cell was calculated by using the absorbance of the formazan crystal of the experimental group for the control group as shown in Equation 2 below.
[수학식 2][Equation 2]
세포 생존율(%) = (실험군의 흡광도 (Absorbance of experimental wells)/대조군의 흡광도 (Absorbance of control wells)) × 100% Cell viability = (Absorbance of experimental wells / Absorbance of control wells) × 100
상기 예시된 THP-1 세포주 이외에 본 발명에서는 여러가지 세포주, 예를 들어 HepG2, NIH 3T3, CHO-K1, HEK 293에 대한 세포 독성 시험을 실시하였으며, 이에 대한 시험 방법은 상기 기술된 방법과 동일하거나 유사하게 진행될 수 있다. 시험 화합물의 세포 독성을 측정한 결과, 시료를 처리하지 않은 대조군에 비하여 시험 화합물 10μM 처리군에서 모든 종류의 세포주에 대하여 세포 생존율이 50% 이상으로서 세포 독성이 거의 나타나지 않았으며 안전한 화합물임을 예상할 수 있다.In addition to the THP-1 cell lines exemplified above, the present invention performed cytotoxicity tests on various cell lines, for example, HepG2, NIH 3T3, CHO-K1, HEK 293, and the test method thereof was the same as or similar to that described above. Can be done. As a result of measuring the cytotoxicity of the test compound, the cell viability of all types of cell lines in the 10 μM treated group of the test compound was 50% or higher, showing little cytotoxicity and a safe compound compared to the control group without the sample. have.
상기 약리 시험 프로토콜에 의해 본 발명의 화합물에 대한 시험 결과를 예시로서 기술하면 하기 표 2와 같다.Test results for the compounds of the present invention by the above pharmacological test protocol are described as Table 2 below.
표 1
약리 시험 실시예 6 화합물 실시예 7 화합물
CCR2 수용체 친화력, IC50 (μM) 0.99 4.44
칼슘이온 유입 억제, IC50 (μM) 0.018 0.12
화학주성 억제, IC50 (μM) 0.009 0.070
CYP450 억제, %@10μM : 3A4 2C9 2C19 2D6 1A2 6.523.614.28.523.5 28.219.09.5-3.56.6
세포 생존율, %@10μM : HepG2 NIH 3T3 CHO-K1 HEK 293 73.570.684.659.3 105.873.080.166.9
Table 1
Pharmacological examination Example 6 Compound Example 7 Compound
CCR2 receptor affinity, IC 50 (μM) 0.99 4.44
Inhibition of calcium ion inflow, IC 50 (μM) 0.018 0.12
Chemotaxis Suppression, IC 50 (μM) 0.009 0.070
CYP450 Inhibition,% @ 10μM: 3A4 2C9 2C19 2D6 1A2 6.523.614.28.523.5 28.219.09.5-3.56.6
Cell viability,% @ 10 μM: HepG2 NIH 3T3 CHO-K1 HEK 293 73.570.684.659.3 105.873.080.166.9
한편, 본 발명의 CCR2 길항제로서의 화합물의 합성을 위해 하기 제조예에 기술된 방법에 따른 중간체를 이용할 수 있다.On the other hand, intermediates according to the methods described in the preparations below can be used for the synthesis of compounds as CCR2 antagonists of the invention.
제조예 1 :Preparation Example 1:
(3-트리플루오로메틸벤조일아미노)-아세트산(3-trifluoromethylbenzoylamino) -acetic acid
Figure PCTKR2010003790-appb-I000011
Figure PCTKR2010003790-appb-I000011
글리신 0.763g(10.16mmol)을 아세토니트릴 20ml에 현탁시키고 2M NaOH 수용액 12.7ml(25.40mmol, 2.5eq.)을 가하였다. 0-3℃로 냉각한 후 3-(트리플루오로메틸)-벤조일 클로라이드 2.12g(10.16mmol, 1.0eq.)을 아세토니트릴 4ml에 희석시켜 천천히 적가하였다. 동일 온도에서 1시간 교반한 후 3N 염산 수용액으로 pH = 2-3으로 조절하였다. 상온에서 정치시킨 후 상층 유기용액을 분리하고, 하층 수용액을 에틸 아세테이트 20ml로 3회 추출하였다. 이렇게 얻은 유기 용액을 모두 모아 무수 황산 마그네슘으로 건조시키고, 감압하에 용매를 제거, 농축하였다. 잔류물을 톨루엔으로 고체화시켜 여과한 후 노르말 헥산으로 세척, 백색 고체로서의 목적 화합물 2.28g(91%)을 수득하였다.0.763 g (10.16 mmol) of glycine was suspended in 20 ml of acetonitrile and 12.7 ml (25.40 mmol, 2.5 eq.) Of 2M NaOH aqueous solution was added. After cooling to 0-3 ° C., 2.12 g (10.16 mmol, 1.0 eq.) Of 3- (trifluoromethyl) -benzoyl chloride was slowly added dropwise with dilution in 4 ml of acetonitrile. The mixture was stirred at the same temperature for 1 hour and then adjusted to pH = 2-3 with 3N aqueous hydrochloric acid solution. After standing at room temperature, the upper organic solution was separated, and the lower aqueous solution was extracted three times with 20 ml of ethyl acetate. The organic solutions thus obtained were combined, dried over anhydrous magnesium sulfate, and the solvent was removed and concentrated under reduced pressure. The residue was solidified with toluene, filtered and washed with normal hexane to afford 2.28 g (91%) of the title compound as a white solid.
1H NMR(400MHz,DMSO-d6) 3.94(2H,d), 7.74(1H,t), 7.93(1H,d), 8.16(1H,d), 8.20(1H,s), 9.12(1H,t) 1 H NMR (400MHz, DMSO-d 6 ) 3.94 (2H, d), 7.74 (1H, t), 7.93 (1H, d), 8.16 (1H, d), 8.20 (1H, s), 9.12 (1H, t)
제조예 2 :Preparation Example 2:
N-[(1-벤질피롤리딘-(3R)-일-카바모일)-메틸]-3-트리플루오로메틸벤즈아미드N-[(1-benzylpyrrolidin- (3R) -yl-carbamoyl) -methyl] -3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000012
Figure PCTKR2010003790-appb-I000012
제조예 1에서 기술된 (3-트리플루오로메틸벤조일아미노)-아세트산 10.74g(43.4mmol) 및 N-메틸모폴린 6.58g(65.10mmol, 1.5eq.)을 아르곤 가스 하에 테트라히드로퓨란 80ml에 용해시켰다. -10℃로 냉각시킨 후 이소부틸 클로로포메이트 7.11g(52.08mmol, 1.2eq.)을 테트라히드로퓨란 10ml에 희석시켜 반응액에 천천히 적가하였다. 동일 온도에서 15분간 교반하고 (3R)-(-)-1-벤질-3-아미노피롤리딘 8.03g(45.57mmol, 1.1eq.)을 테트라히드로퓨란 10ml에 희석시켜 천천히 적가하였다. -10℃에서 1시간 동안 교반한 후 정제수 100ml를 투입하였다. 에틸 아세테이트 100ml로 3회 연속 추출하여 유기층을 회수하였다. 무수 황산 마그네슘으로 건조시키고 감압 농축하였다. 잔류물을 t-부틸 메틸 에테르로 고체화시켜 여과한 후 백색 고체로서의 목적 화합물 12.18g(69%)을 수득하였다.10.74 g (43.4 mmol) of (3-trifluoromethylbenzoylamino) -acetic acid and 6.58 g (65.10 mmol, 1.5 eq.) Of N-methylmorpholine described in Preparation Example 1 were dissolved in 80 ml of tetrahydrofuran under argon gas. I was. After cooling to −10 ° C., 7.11 g (52.08 mmol, 1.2 eq.) Of isobutyl chloroformate was diluted in 10 ml of tetrahydrofuran and slowly added dropwise to the reaction solution. The mixture was stirred at the same temperature for 15 minutes, and 8.03 g (45.57 mmol, 1.1 eq.) Of (3R)-(-)-1-benzyl-3-aminopyrrolidine was slowly added dropwise to 10 ml of tetrahydrofuran. After stirring at −10 ° C. for 1 hour, 100 ml of purified water was added thereto. The organic layer was recovered by three successive extractions with 100 ml of ethyl acetate. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was solidified with t-butyl methyl ether to give 12.18 g (69%) of the desired compound as a white solid.
1H NMR(400MHz,DMSO-d6) 1.62-1.66(1H,m), 2.26-2.36(2H,m), 2.54-2.59(1H,m), 2.63-2.66(1H,m), 2.89-2.93(1H,m), 3.62(2H,d), 4.10(2H,d), 4.46-4.90(1H,m), 6.45(1H,br s), 7.15(1H,br s), 7.29-7.34(5H,m), 7.59(1H,t), 7.78(1H,d), 8.00(1H,d), 8.11(1H,s) 1 H NMR (400 MHz, DMSO-d 6 ) 1.62-1.66 (1H, m), 2.26-2.36 (2H, m), 2.54-2.59 (1H, m), 2.63-2.66 (1H, m), 2.89-2.93 (1H, m), 3.62 (2H, d), 4.10 (2H, d), 4.46-4.90 (1H, m), 6.45 (1H, br s), 7.15 (1H, br s), 7.29-7.34 (5H , m), 7.59 (1H, t), 7.78 (1H, d), 8.00 (1H, d), 8.11 (1H, s)
제조예 3 :Preparation Example 3:
N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드N- (pyrrolidin- (3R) -yl-carbamoylmethyl) -3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000013
Figure PCTKR2010003790-appb-I000013
제조예 2에서 기술된 N-[(1-벤질피롤리딘-(3R)-일-카바모일)-메틸]-3-트리플루오로메틸벤즈아미드 9.00g(22.20mmol)을 메탄올 45ml에 용해시키고 팔라듐 히드록시드(Pd(OH)2) 0.05g(촉매량)을 투입하였다. 반응액을 수소 가스 1기압 환경하에 상온에서 일야 교반하였다. 반응액을 규조토를 사용하여 여과, 여과액을 회수하여 감압 농축하였다. 얻어진 잔류물을 실리카겔을 이용한 크로마토그래피에 의해 정제(이동상 : 메탄올)하여, 목적 화합물을 백색 고체로서 5.74g(82%) 수득하였다.9.00 g (22.20 mmol) of N-[(1-benzylpyrrolidin- (3R) -yl-carbamoyl) -methyl] -3-trifluoromethylbenzamide described in Preparation Example 2 were dissolved in 45 ml of methanol 0.05 g (catalyst amount) of palladium hydroxide (Pd (OH) 2 ) was added thereto. The reaction solution was stirred overnight at room temperature under an atmosphere of hydrogen gas at 1 atmosphere. The reaction solution was filtered using diatomaceous earth, and the filtrate was recovered and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (mobile phase: methanol) to give 5.74 g (82%) of the title compound as a white solid.
1H NMR(400MHz,DMSO-d6) 1.47-1.52(1H,m), 1.86-1.91(1H,m), 2.68-2.74(1H,m), 2.79-2.84(1H,m), 2.86-2.91(1H,m), 3.16(2H,s), 3.86(2H,d), 4.05-4.13(1H,m), 7.73(1H,t), 7.93(1H,d), 8.00(1H,d), 8.17(1H,d), 8.22(1H,s), 8.98(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.47-1.52 (1H, m), 1.86-1.91 (1H, m), 2.68-2.74 (1H, m), 2.79-2.84 (1H, m), 2.86-2.91 (1H, m), 3.16 (2H, s), 3.86 (2H, d), 4.05-4.13 (1H, m), 7.73 (1H, t), 7.93 (1H, d), 8.00 (1H, d), 8.17 (1H, d), 8.22 (1H, s), 8.98 (1H, t)
제조예 4 :Preparation Example 4:
N-{[1-(2-(4-tert-부톡시카르보닐피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-tert-butoxycarbonylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide
Figure PCTKR2010003790-appb-I000014
Figure PCTKR2010003790-appb-I000014
제조예 3에서 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 1.00g(3.17mmol)과 탄산칼륨 1.32g(9.52mmol, 3.0eq.)을 아세토니트릴 25ml에 투입하고, 아세토니트릴 5ml에 희석시킨 tert-부틸 4-(2-(메틸술포닐옥시)에틸)피페라진-1-카복실레이트 0.98g(3.17mmol, 1.0eq.)을 상온에서 천천히 적가하였다. 상온에서 80℃로 가온하여 24시간 교반한 다음, 정제수 25ml를 가하고 에틸 아세테이트 25ml로 3회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조시킨 다음, 감압 농축하여 얻어진 잔류물을 실리카겔 상에서 크로마토그래피로 정제(이동상 : 디클로로메탄/메탄올 = 10:1)하여 백색 고체로서의 목적 화합물 1.14g(68%)을 수득하였다.1.00 g (3.17 mmol) of N- (pyrrolidin- (3R) -yl-carbamoylmethyl) -3-trifluoromethylbenzamide described in Preparation Example 3 and 1.32 g (9.52 mmol, 3.0 eq.) Of potassium carbonate. ) Into 25 ml of acetonitrile and 0.98 g (3.17 mmol, 1.0 eq.) Of tert-butyl 4- (2- (methylsulfonyloxy) ethyl) piperazine-1-carboxylate diluted in 5 ml of acetonitrile. Was slowly added dropwise. After warming to room temperature to 80 ℃ and stirred for 24 hours, 25 ml of purified water was added and extracted three times with 25 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 10: 1) to obtain 1.14 g (68%) of the title compound as a white solid. It was.
1H NMR(400MHz,CDCl3) 1.45(9H,s), 1.64-1.72(1H,m), 2.28-2.80(12H,m), 2.95-3.04(1H,m), 3.36-3.52(4H,m), 4.07-4.13(2H,m), 4.47-4.52(1H,m), 6.73-6.84(1H,m), 7.28-7.32(1H,m), 7.58(1H,t), 7.77(1H,d), 8.02(1H,d), 8.12(1H,s) 1 H NMR (400 MHz, CDCl 3 ) 1.45 (9H, s), 1.64-1.72 (1H, m), 2.28-2.80 (12H, m), 2.95-3.04 (1H, m), 3.36-3.52 (4H, m ), 4.07-4.13 (2H, m), 4.47-4.52 (1H, m), 6.73-6.84 (1H, m), 7.28-7.32 (1H, m), 7.58 (1H, t), 7.77 (1H, d ), 8.02 (1H, d), 8.12 (1H, s)
제조예 5 :Preparation Example 5
N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide hydrochloride
Figure PCTKR2010003790-appb-I000015
Figure PCTKR2010003790-appb-I000015
제조예 4에서 기술된 N-{[1-(2-(4-tert-부톡시카르보닐피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 0.65g(1.23mmol)을 염산으로 포화된 에탄올 3ml에 용해시켰다. 상온에서 1.5시간 교반한 후 감압 농축하고, 고진공하에 일야 건조시킨 후 노란색 시럽으로의 목적 화합물 0.56g(98%)을 수득하였다.N-{[1- (2- (4-tert-butoxycarbonylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} as described in Preparation Example 4. 0.65 g (1.23 mmol) of 3-trifluoromethylbenzamide was dissolved in 3 ml of ethanol saturated with hydrochloric acid. After stirring at room temperature for 1.5 hours, the mixture was concentrated under reduced pressure, dried under high vacuum overnight, and 0.56 g (98%) of the title compound was obtained as a yellow syrup.
MS (M+1)+ : 428.4MS (M + 1) + : 428.4
제조예 6 :Preparation Example 6:
N-{[1-(2-히드록시프로필)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2-hydroxypropyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000016
Figure PCTKR2010003790-appb-I000016
제조예 3에서 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 200mg(0.63mmol) 및 탄산칼륨 263mg(1.90mmol, 3.0eq.)을 아세토니트릴 10ml에 상온에서 현탁시켰다. 프로필렌 옥시드 122mg(2.09mmol, 3.0eq.)을 투입한 후 가열 환류하여 일야 교반하였다. 상온으로 냉각시킨 후 정제수 15ml를 가한 다음 에틸 아세테이트 15ml로 2회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조한 다음, 감압 농축하였다. 얻어진 잔류물을 실리카겔을 이용한 크로마토그래피로 정제(이동상 : 디클로로메탄/메탄올 = 5:1)하여 노란색 고체로서의 목적 화합물 154mg(65%)을 수득하였다.200 mg (0.63 mmol) of N- (pyrrolidin- (3R) -yl-carbamoylmethyl) -3-trifluoromethylbenzamide and 263 mg (1.90 mmol, 3.0 eq.) Of potassium carbonate described in Preparation Example 3 were prepared. It was suspended in 10 ml of acetonitrile at room temperature. 122 mg (2.09 mmol, 3.0 eq.) Of propylene oxide was added, and the mixture was heated to reflux and stirred overnight. After cooling to room temperature, 15 ml of purified water was added, followed by extraction twice with 15 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 5: 1) to give 154 mg (65%) of the title compound as a yellow solid.
1H NMR(400MHz,DMSO-d6) 1.02(3H,d), 1.48-1.59(1H,m), 2.00-2.10(1H,m), 2.22-2.40(4H,m), 2.50-2.58(2H,m), 3.15(2H,d), 3.60-3.71(1H,m), 3.85(2H,d), 4.08-4.20(2H,m), 4.30(1H,t), 7.73(1H,t), 7.91(1H,d), 8.05-8.12(1H,m), 8.16(1H,d), 8.21(1H,s), 8.95-9.01(1H,m) 1 H NMR (400 MHz, DMSO-d 6 ) 1.02 (3H, d), 1.48-1.59 (1H, m), 2.00-2.10 (1H, m), 2.22-2.40 (4H, m), 2.50-2.58 (2H , m), 3.15 (2H, d), 3.60-3.71 (1H, m), 3.85 (2H, d), 4.08-4.20 (2H, m), 4.30 (1H, t), 7.73 (1H, t), 7.91 (1H, d), 8.05-8.12 (1H, m), 8.16 (1H, d), 8.21 (1H, s), 8.95-9.01 (1H, m)
제조예 7 :Preparation Example 7:
N-{[1-(2-히드록시부틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2-hydroxybutyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000017
Figure PCTKR2010003790-appb-I000017
제조예 3에서 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 200mg(0.63mmol), 탄산칼륨 263mg(1.90mmol, 3.0eq.) 및 1,2-에폭시부탄 229mg(3.17mmol, 5.0eq.)을 사용하여 제조예 6과 동일한 방법으로 노란색 액체로서의 목적 화합물 110mg(45%)을 수득하였다.200 mg (0.63 mmol) of N- (pyrrolidin- (3R) -yl-carbamoylmethyl) -3-trifluoromethylbenzamide described in Preparation Example 3, 263 mg (1.90 mmol, 3.0 eq.) Of potassium carbonate and 110 mg (45%) of the title compound as a yellow liquid were obtained in the same manner as in Preparation Example 6, using 229 mg of 1,2-epoxybutane (3.17 mmol, 5.0 eq.).
1H NMR(400MHz,DMSO-d6) 0.85(3H,t), 1.40-1.60(2H,m), 2.00-2.10(1H,m), 2.30-2.42(4H,m), 2.59-2.69(2H,m), 3.85(2H,d), 4.08(2H,q), 4.11-4.20(1H,m), 4.22(1H,t), 7.73(1H,t), 7.91(1H,d), 8.07(1H,d), 8.16(1H,d), 8.21(1H,s), 8.96(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 0.85 (3H, t), 1.40-1.60 (2H, m), 2.00-2.10 (1H, m), 2.30-2.42 (4H, m), 2.59-2.69 (2H , m), 3.85 (2H, d), 4.08 (2H, q), 4.11-4.20 (1H, m), 4.22 (1H, t), 7.73 (1H, t), 7.91 (1H, d), 8.07 ( 1H, d), 8.16 (1H, d), 8.21 (1H, s), 8.96 (1H, t)
제조예 8 :Preparation Example 8
N-{[1-(2-히드록시-2-메틸프로필)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2-hydroxy-2-methylpropyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000018
Figure PCTKR2010003790-appb-I000018
제조예 3에서 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 1.00g(3.17mmol), 탄산칼륨 1.32g(9.55mmol, 3.0eq.) 및 이소부틸렌 옥시드 690mg(9.57mmol, 3.0eq.)을 사용하여 제조예 6과 동일한 방법으로 노란색 고체로서의 목적 화합물 700mg(57%)을 수득하였다.1.00 g (3.17 mmol) of N- (pyrrolidin- (3R) -yl-carbamoylmethyl) -3-trifluoromethylbenzamide described in Preparation Example 3, 1.32 g (9.55 mmol, 3.0 eq.) Of potassium carbonate. ) And isobutylene oxide 690 mg (9.57 mmol, 3.0 eq.) To obtain 700 mg (57%) of the target compound as a yellow solid in the same manner as in Preparation Example 6.
1H NMR(400MHz,DMSO-d6) 1.08(6H,s), 1.50-1.60(1H,m), 1.99-2.09(1H,m), 2.28-2.37(2H,m), 2.45-2.53(2H,m), 2.69-2.80(2H,m), 3.88(2H,d), 4.05(1H,s), 4.11-4.20(1H,m), 7.74(1H,t), 7.92(1H,d), 8.04(1H,d), 8.18(1H,d), 8.23(1H,s), 8.99(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.08 (6H, s), 1.50-1.60 (1H, m), 1.99-2.09 (1H, m), 2.28-2.37 (2H, m), 2.45-2.53 (2H , m), 2.69-2.80 (2H, m), 3.88 (2H, d), 4.05 (1H, s), 4.11-4.20 (1H, m), 7.74 (1H, t), 7.92 (1H, d), 8.04 (1H, d), 8.18 (1H, d), 8.23 (1H, s), 8.99 (1H, t)
제조예 9 :Preparation Example 9:
(4-(2-히드록시-2-메틸프로필)피페라진-1-일)페닐메탄온(4- (2-hydroxy-2-methylpropyl) piperazin-1-yl) phenylmethanone
Figure PCTKR2010003790-appb-I000019
Figure PCTKR2010003790-appb-I000019
1-벤조일피페라진 500mg(2.63mmol) 및 탄산칼륨 1.10g(7.96mmol, 3.0eq.)을 아세토니트릴 20ml에 상온에서 현탁시켰다. 이소부틸렌 옥시드 570mg(7.90mmol, 3.0eq.)을 투입한 후 가열 환류하여 일야 교반하였다. 상온으로 냉각시킨 후 정제수 30ml를 가한 다음 에틸 아세테이트 30ml로 2회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조한 다음, 감압 농축하였다. 얻어진 잔류물을 실리카겔을 이용한 크로마토그래피로 정제(이동상 : 디클로로메탄/메탄올 = 20:1)하여 미황색 고체로서의 목적 화합물 276mg(40%)을 수득하였다.500 mg (2.63 mmol) of 1-benzoylpiperazine and 1.10 g (7.96 mmol, 3.0 eq.) Of potassium carbonate were suspended in 20 ml of acetonitrile at room temperature. 570 mg (7.90 mmol, 3.0 eq.) Of isobutylene oxide was added thereto, followed by heating to reflux for stirring overnight. After cooling to room temperature, 30 ml of purified water was added and extracted twice with 30 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 20: 1) to give 276 mg (40%) of the title compound as a pale yellow solid.
1H NMR(400MHz,DMSO-d6) 1.10(6H,s), 2.23(2H,s), 2.43-2.52(2H,m), 2.53-2.62(2H,m), 3.35-3.45(2H,m), 3.55-3.65(2H,m), 4.13(1H,s), 7.35-7.38(2H,m), 7.43-7.46(3H,m) 1 H NMR (400 MHz, DMSO-d 6 ) 1.10 (6H, s), 2.23 (2H, s), 2.43-2.52 (2H, m), 2.53-2.62 (2H, m), 3.35-3.45 (2H, m ), 3.55-3.65 (2H, m), 4.13 (1H, s), 7.35-7.38 (2H, m), 7.43-7.46 (3H, m)
제조예 10 :Preparation Example 10
1-(4-벤조일피페라진-1-일)프로판-2-온1- (4-benzoylpiperazin-1-yl) propan-2-one
Figure PCTKR2010003790-appb-I000020
Figure PCTKR2010003790-appb-I000020
1-벤조일피페라진 0.10g(0.53mmol)과 탄산칼륨 0.22g(1.58mmol, 3.0eq.)을 아세토니트릴 5ml에 투입하고, 클로로아세톤 0.05g(0.53mmol, 1.0eq.)을 상온에서 천천히 적가하였다. 1시간 교반한 다음, 정제수 5ml를 가하고 에틸 아세테이트 10ml로 3회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조시킨 다음, 감압 농축하여 얻어진 잔류물을 실리카겔 상에서 크로마토그래피로 정제(이동상 : 디클로로메탄/메탄올 = 10:1)하여 노란색 시럽으로서의 목적 화합물 0.11g(83%)을 수득하였다.0.10 g (0.53 mmol) of 1-benzoylpiperazine and 0.22 g (1.58 mmol, 3.0 eq.) Of potassium carbonate were added to 5 ml of acetonitrile, and 0.05 g (0.53 mmol, 1.0 eq.) Of chloroacetone was slowly added dropwise at room temperature. . After stirring for 1 hour, 5 ml of purified water was added thereto, and the mixture was extracted three times with 10 ml of ethyl acetate. The organic layer was collected, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 10: 1) to obtain 0.11 g (83%) of the title compound as a yellow syrup. It was.
1H NMR(400MHz,CDCl3) 2.18(3H,s), 2.41-2.69(4H,m), 3.27(2H,s), 3.42-3.54(2H,m), 3.81-3.93(2H,m), 7.40-7.46(5H,m) 1 H NMR (400 MHz, CDCl 3 ) 2.18 (3H, s), 2.41-2.69 (4H, m), 3.27 (2H, s), 3.42-3.54 (2H, m), 3.81-3.93 (2H, m), 7.40-7.46 (5H, m)
제조예 11 :Preparation Example 11
3-(4-벤조일피페라진-1-일)부탄-2-온3- (4-benzoylpiperazin-1-yl) butan-2-one
Figure PCTKR2010003790-appb-I000021
Figure PCTKR2010003790-appb-I000021
1-벤조일피페라진 0.05g(0.26mmol), 탄산칼륨 0.11g(0.79mmol, 3.0eq.), 3-클로로-2-부탄온 0.03g(0.26mmol, 1.0eq.)을 사용하여 제조예 10과 동일한 방법으로 노란색 시럽으로서의 목적 화합물 0.05g(73%)을 수득하였다.Preparation Example 10 using 0.05 g (0.26 mmol) of 1-benzoylpiperazine, 0.11 g (0.79 mmol, 3.0 eq.) Of potassium carbonate, and 0.03 g (0.26 mmol, 1.0 eq.) Of 3-chloro-2-butanone In the same manner, 0.05 g (73%) of the target compound as a yellow syrup was obtained.
1H NMR(400MHz,CDCl3) 1.17(3H,d), 2.25(3H,s), 2.38-2.72(4H,m), 3.20(1H,q), 3.38-3.53(2H,m), 3.74-3.89(2H,m), 7.40-7.48(5H,m) 1 H NMR (400MHz, CDCl 3 ) 1.17 (3H, d), 2.25 (3H, s), 2.38-2.72 (4H, m), 3.20 (1H, q), 3.38-3.53 (2H, m), 3.74- 3.89 (2H, m), 7.40-7.48 (5H, m)
제조예 12 :Preparation Example 12
tert-부틸 4-(2-클로로아세틸)피페라진-1-카복실레이트tert-butyl 4- (2-chloroacetyl) piperazine-1-carboxylate
Figure PCTKR2010003790-appb-I000022
Figure PCTKR2010003790-appb-I000022
tert-부틸 1-피페라진카복실레이트 2.00g(10.74mmol), 트리에틸아민 1.30g(12.89mmol, 1.2eq.)을 아르곤 가스 하에 디클로로메탄 25ml에 용해시켰다. 3℃로 냉각시킨 후 클로로아세틸 클로라이드 1.33g(11.81mmol, 1.1eq.)을 디클로로메탄 5ml에 희석시켜 반응액에 천천히 적가하였다. 3℃에서 1시간 동안 교반한 후 정제수 20ml를 가하고 유기층을 분리, 다시 수층을 디클로로메탄 40ml로 1회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조하고 감압 농축하였다. 잔류물을 실리카겔을 이용한 크로마토그래피로 정제(이동상 : 에틸 아세테이트/헥산 = 1:2)하여 노란색 시럽으로서 목적화합물 2.00g(71%)을 수득했다.2.00 g (10.74 mmol) of tert-butyl 1-piperazinecarboxylate and 1.30 g (12.89 mmol, 1.2 eq.) of triethylamine were dissolved in 25 ml of dichloromethane under argon gas. After cooling to 3 ° C., 1.33 g (11.81 mmol, 1.1 eq.) Of chloroacetyl chloride was diluted in 5 ml of dichloromethane and slowly added dropwise to the reaction solution. After stirring at 3 ° C. for 1 hour, 20 ml of purified water was added, the organic layer was separated, and the aqueous layer was extracted once with 40 ml of dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: ethyl acetate / hexane = 1: 2) to give 2.00 g (71%) of the title compound as a yellow syrup.
1H NMR(400MHz,CDCl3) 1.48(9H,s), 3.45(2H,t), 3.51(4H,s), 3.61(2H,t), 4.09(2H,s) 1 H NMR (400 MHz, CDCl 3 ) 1.48 (9H, s), 3.45 (2H, t), 3.51 (4H, s), 3.61 (2H, t), 4.09 (2H, s)
제조예 13 :Preparation Example 13
N-{[1-(2-(4-tert-부톡시카르보닐피페라진-1-일)-2-옥소-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-tert-butoxycarbonylpiperazin-1-yl) -2-oxo-ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl}- 3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000023
Figure PCTKR2010003790-appb-I000023
제조예 3에서 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 1.00g(3.17mmol)과 탄산칼륨 1.32g(9.52mmol, 3.0eq.)을 아세토니트릴 25ml에 투입하고, 제조예 12에서 기술된 tert-부틸 4-(2-클로로아세틸)피페라진-1-카복실레이트 0.83g(3.17mmol, 1.0eq.)을 아세토니트릴 5ml에 희석시켜 상온에서 천천히 적가하였다. 상온에서 80℃로 가온하여 2시간 교반한 다음, 정제수 25ml를 가하고 에틸 아세테이트 25ml로 3회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조시킨 다음, 감압 농축하여 얻어진 잔류물을 실리카겔 상에서 크로마토그래피로 정제(이동상 : 디클로로메탄/메탄올 = 10:1)하여 백색 고체로서의 목적 화합물 1.12g(65%)을 수득하였다.1.00 g (3.17 mmol) of N- (pyrrolidin- (3R) -yl-carbamoylmethyl) -3-trifluoromethylbenzamide described in Preparation Example 3 and 1.32 g (9.52 mmol, 3.0 eq.) Of potassium carbonate. ) Was added to 25 ml of acetonitrile, and 0.83 g (3.17 mmol, 1.0 eq.) Of tert-butyl 4- (2-chloroacetyl) piperazine-1-carboxylate described in Preparation 12 was diluted with 5 ml of acetonitrile. Slowly added dropwise at room temperature. After warming to 80 ° C. at room temperature and stirring for 2 hours, 25 ml of purified water was added thereto and extracted three times with 25 ml of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 10: 1) to give 1.12 g (65%) of the title compound as a white solid. It was.
1H NMR(400MHz,CDCl3) 1.48(9H,s), 1.72-1.81(1H,m), 2.17-2.29(1H,m), 2.52-2.62(1H,m), 2.73-2.82(1H,m), 2.85-2.95(1H,m), 3.00(1H,q), 3.39(2H,d), 3.40-3.46(4H,m), 3.47-3.55(4H,m), 4.11-4.23(2H,m), 4.46-4.52(1H,m), 7.27-7.36(1H,m), 7.44(1H,d), 7.59(1H,t), 7.77(1H,d), 8.03(1H,d), 8.13(1H,s) 1 H NMR (400 MHz, CDCl 3 ) 1.48 (9H, s), 1.72-1.81 (1H, m), 2.17-2.29 (1H, m), 2.52-2.62 (1H, m), 2.73-2.82 (1H, m ), 2.85-2.95 (1H, m), 3.00 (1H, q), 3.39 (2H, d), 3.40-3.46 (4H, m), 3.47-3.55 (4H, m), 4.11-4.23 (2H, m) ), 4.46-4.52 (1H, m), 7.27-7.36 (1H, m), 7.44 (1H, d), 7.59 (1H, t), 7.77 (1H, d), 8.03 (1H, d), 8.13 ( 1H, s)
제조예 14 :Preparation Example 14
N-{[1-(2-(피페라진-1-일)-2-옥소-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염N-{[1- (2- (piperazin-1-yl) -2-oxo-ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide Hydrochloride
Figure PCTKR2010003790-appb-I000024
Figure PCTKR2010003790-appb-I000024
제조예 13에서 기술된 N-{[1-(2-(4-tert-부톡시카르보닐피페라진-1-일)-2-옥소-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 1.12g(2.07mmol)을 염산으로 포화된 에탄올 5ml에 용해시켰다. 상온에서 1.5시간 교반한 후 감압 농축하고, 고진공하에 일야 건조시킨 후 노란색 시럽으로의 목적 화합물 0.93g(94%)을 수득하였다.N-{[1- (2- (4-tert-butoxycarbonylpiperazin-1-yl) -2-oxo-ethyl) -pyrrolidin- (3R) -yl-carba as described in Preparation Example 13 Moyl] -methyl} -3-trifluoromethylbenzamide 1.12 g (2.07 mmol) was dissolved in 5 ml of ethanol saturated with hydrochloric acid. After stirring at room temperature for 1.5 hours, the mixture was concentrated under reduced pressure, dried under high vacuum overnight, and 0.93 g (94%) of the title compound was obtained as a yellow syrup.
MS (M+1)+ 478.7MS (M + 1) + 478.7
본 발명은 하기 실시예를 통해 더욱 구체적으로 예시된다. 그러나 이러한 예시로써 본 발명의 범위가 한정되지는 않는다.The invention is illustrated more specifically through the following examples. However, the scope of the present invention is not limited to these examples.
실시예EXAMPLE
실시예 1 :Example 1:
N-{[1-(2-(1-(페닐아미노카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (1- (phenylaminocarbonyl) -piperazin-4-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Rommethylbenzamide
Figure PCTKR2010003790-appb-I000025
Figure PCTKR2010003790-appb-I000025
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol) 및 N,N-디이소프로필에틸아민 40mg(0.32mmol, 3.0eq.), 페닐 이소시아네이트 10mg(0.11mmol, 1.0eq.)를 아르곤 가스 하에 디클로로메탄 5ml에 용해시켰다. 상온에서 2시간 교반한 다음 정제수 10ml를 가하고 유기층을 분리, 다시 수층을 디클로로메탄 10ml로 1회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조하고 감압 농축하였다. 잔류물을 실리카겔을 이용한 크로마토그래피로 정제(이동상 : 디클로로메탄/메탄올 = 10:1)하여 백색 고체로서 목적 화합물 50mg(67%)을 수득했다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 50 mg (0.11 mmol) of amide hydrochloride and 40 mg (0.32 mmol, 3.0 eq.) Of N, N-diisopropylethylamine and 10 mg (0.11 mmol, 1.0 eq.) Of phenyl isocyanate were dissolved in 5 ml of dichloromethane under argon gas. After stirring for 2 hours at room temperature, 10 ml of purified water was added, the organic layer was separated, and the aqueous layer was extracted once with 10 ml of dichloromethane. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 10: 1) to give 50 mg (67%) of the title compound as a white solid.
1H NMR(400MHz,CDCl3) 1.67-1.78(1H,m), 2.28-2.40(2H,m), 2.48-2.59(7H,m), 2.60-2.78(2H,m), 2.84(1H,d), 3.03-3.12(1H,m), 3.45-3.57(4H,m), 4.05-4.20(2H,m), 4.47-4.52(1H,m), 6.60(1H,s), 7.05(1H,d), 7.23(2H,d), 7.32(1H,d), 7.32-7.36(1H,m), 7.58(1H,t), 7.77(1H,d), 8.01(1H,d), 8.11(1H,s) 1 H NMR (400 MHz, CDCl 3 ) 1.67-1.78 (1H, m), 2.28-2.40 (2H, m), 2.48-2.59 (7H, m), 2.60-2.78 (2H, m), 2.84 (1H, d ), 3.03-3.12 (1H, m), 3.45-3.57 (4H, m), 4.05-4.20 (2H, m), 4.47-4.52 (1H, m), 6.60 (1H, s), 7.05 (1H, d ), 7.23 (2H, d), 7.32 (1H, d), 7.32-7.36 (1H, m), 7.58 (1H, t), 7.77 (1H, d), 8.01 (1H, d), 8.11 (1H, s)
실시예 2 :Example 2:
N-{[1-(2-(1-(p-톨릴아미노카르보닐)-피페라진-4-일)-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (1- (p-tolylaminocarbonyl) -piperazin-4-yl) -ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000026
Figure PCTKR2010003790-appb-I000026
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol), N,N-디이소프로필에틸아민 40mg(0.32mmol, 3.0eq.), 이소시안산 m-톨릴 에스테르 14mg(0.11mmol, 1.0eq.)을 사용하여 실시예 1과 동일한 방법으로 백색 고체로서의 목적 화합물 45mg(75%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 Example 1 using 50 mg (0.11 mmol) of amide hydrochloride, 40 mg (0.32 mmol, 3.0 eq.) Of N, N-diisopropylethylamine, and 14 mg (0.11 mmol, 1.0 eq.) Of isocyanic acid m-tolyl ester In the same manner, 45 mg (75%) of the title compound as a white solid were obtained.
1H NMR(400MHz,CDCl3) 1.63-1.75(1H,m), 2.23-2.30(2H,m), 2.32(3H,s), 2.51-2.60(7H,m), 2.62-2.73(2H,m), 2.79(1H,d), 3.02(1H,t), 3.51(4H,t), 4.08-4.15(2H,m), 4.47-4.55(1H,m), 6.37(1H,s), 6.74(1H,d), 6.86(1H,d), 7.11(1H,d), 7.14-7.21(2H,m), 7.23(1H,s), 7.59(1H,t), 7.78(1H,d), 8.01(1H,d), 8.11(1H,s) 1 H NMR (400 MHz, CDCl 3 ) 1.63-1.75 (1H, m), 2.23-2.30 (2H, m), 2.32 (3H, s), 2.51-2.60 (7H, m), 2.62-2.73 (2H, m ), 2.79 (1H, d), 3.02 (1H, t), 3.51 (4H, t), 4.08-4.15 (2H, m), 4.47-4.55 (1H, m), 6.37 (1H, s), 6.74 ( 1H, d), 6.86 (1H, d), 7.11 (1H, d), 7.14-7.21 (2H, m), 7.23 (1H, s), 7.59 (1H, t), 7.78 (1H, d), 8.01 (1H, d), 8.11 (1H, s)
실시예 3 :Example 3:
N-{[1-(2-(1-(4-클로로페닐아미노카르보닐)-피페라진-4-일)-에틸)-피롤리딘-(3R)-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (1- (4-Chlorophenylaminocarbonyl) -piperazin-4-yl) -ethyl) -pyrrolidine- (3R) -carbamoyl] -methyl} -3- Trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000027
Figure PCTKR2010003790-appb-I000027
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol), N,N-디이소프로필에틸아민 40mg(0.32mmol, 3.0eq.), 이소시안산 4-클로로페닐 에스테르 17mg(0.11mmol, 1.0eq.)을 사용하여 실시예 1과 동일한 방법으로 백색 고체로서의 목적 화합물 50mg(83%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 Example 1 using 50 mg (0.11 mmol) of amide hydrochloride, 40 mg (0.32 mmol, 3.0 eq.) Of N, N-diisopropylethylamine, and 17 mg (0.11 mmol, 1.0 eq.) Of isocyanic acid 4-chlorophenyl ester In the same manner as the 50 mg (83%) of the target compound as a white solid.
1H NMR(400MHz,CDCl3) 1.67-1.78(1H,m), 2.28-2.40(2H,m), 2.48-2.59(7H,m), 2.60-2.78(2H,m), 2.84(1H,d), 3.03-3.12(1H,m), 3.45-3.57(4H,m), 4.05-4.20(2H,m), 4.47-4.52(1H,m), 6.60(1H,s), 7.05(1H,d), 7.23(2H,d), 7.32(1H,d), 7.33-7.36(1H,m), 7.58(1H,t), 7.77(1H,d), 8.01(1H,d), 8.11(1H,s) 1 H NMR (400 MHz, CDCl 3 ) 1.67-1.78 (1H, m), 2.28-2.40 (2H, m), 2.48-2.59 (7H, m), 2.60-2.78 (2H, m), 2.84 (1H, d ), 3.03-3.12 (1H, m), 3.45-3.57 (4H, m), 4.05-4.20 (2H, m), 4.47-4.52 (1H, m), 6.60 (1H, s), 7.05 (1H, d ), 7.23 (2H, d), 7.32 (1H, d), 7.33-7.36 (1H, m), 7.58 (1H, t), 7.77 (1H, d), 8.01 (1H, d), 8.11 (1H, s)
실시예 4 :Example 4:
N-{[1-(2-(1-(메톡시카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (1- (methoxycarbonyl) -piperazin-4-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Rommethylbenzamide
Figure PCTKR2010003790-appb-I000028
Figure PCTKR2010003790-appb-I000028
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol) 및 탄산칼륨 60mg(0.43mmol, 4.0eq.)을 아세토니트릴 3ml에 상온에서 현탁시킨 후, 메틸 클로로포르메이트 10mg(0.11mmol, 1.0eq.)을 아세토니트릴 1ml에 희석시켜 천천히 투입하였다. 가열 환류시켜 1시간 동안 교반한 후 감압농축하였다. 얻어진 잔류물에 정제수 10ml를 가한 다음 에틸 아세테이트 10ml로 2회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조시키고 감압 농축하였다. 얻어진 잔류물을 실리카겔을 이용한 크로마토그래피에 의해 정제(이동상 : 디클로로메탄/메탄올 = 5:1)하여 목적 화합물을 미백색 고체로서 40mg(80%) 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 50 mg (0.11 mmol) of amide hydrochloride and 60 mg (0.43 mmol, 4.0 eq.) Of potassium carbonate were suspended in 3 ml of acetonitrile at room temperature, and then 10 mg (0.11 mmol, 1.0 eq.) Of methyl chloroformate was diluted in 1 ml of acetonitrile. Slowly added. The mixture was heated to reflux, stirred for 1 hour, and then concentrated under reduced pressure. 10 ml of purified water was added to the obtained residue, followed by extraction twice with 10 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 5: 1) to obtain 40 mg (80%) of the target compound as a white white solid.
1H NMR(400MHz,CDCl3) 1.68-1.79(1H,m), 2.29-2.40(2H,m), 2.41-2.49(4H,m), 2.53-2.57(2H,m), 2.58-2.64(1H,m), 2.68-2.77(2H,m), 2.80-2.91(1H,m), 3.05-3.17(1H,m), 3.44-3.56(4H,m), 3.70(3H,s), 4.06-4.18(2H,m), 4.47-4.58(1H,m), 6.62-6.84(1H,m), 7.12-7.21(1H,m), 7.60(1H,t), 7.78(1H,d), 8.04(1H,d), 8.13(1H,s) 1 H NMR (400 MHz, CDCl 3 ) 1.68-1.79 (1H, m), 2.29-2.40 (2H, m), 2.41-2.49 (4H, m), 2.53-2.57 (2H, m), 2.58-2.64 (1H , m), 2.68-2.77 (2H, m), 2.80-2.91 (1H, m), 3.05-3.17 (1H, m), 3.44-3.56 (4H, m), 3.70 (3H, s), 4.06-4.18 (2H, m), 4.47-4.58 (1H, m), 6.62-6.84 (1H, m), 7.12-7.21 (1H, m), 7.60 (1H, t), 7.78 (1H, d), 8.04 (1H d), 8.13 (1H, s)
실시예 5 :Example 5:
N-{[1-(2-(1-(에톡시카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (1- (ethoxycarbonyl) -piperazin-4-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Rommethylbenzamide
Figure PCTKR2010003790-appb-I000029
Figure PCTKR2010003790-appb-I000029
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol), 탄산칼륨 60mg(0.43mmol, 4.0eq.), 에틸 클로로포르메이트 10mg(0.11mmol, 1.0eq.)을 사용하여 실시예 4와 동일한 방법으로 백색 고체로서의 목적 화합물 40mg(74%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 40 mg of the target compound as a white solid in the same manner as in Example 4 using 50 mg (0.11 mmol) of amide hydrochloride, 60 mg (0.43 mmol, 4.0 eq.) Of potassium carbonate, and 10 mg (0.11 mmol, 1.0 eq.) Of ethyl chloroformate ( 74%) was obtained.
1H NMR(400MHz,CDCl3) 1.26(3H,t), 1.63-1.78(1H,m), 2.23-2.38(2H,m), 2.41-2.49(4H,m), 2.50-2.57(2H,m), 2.58-2.73(3H,m), 2.80(1H,d), 2.97-3.08(1H,m), 3.42-3.53(4H,m), 4.11-4.20(4H,m), 4.48-4.53(1H,m), 7.17(1H,d), 7.41-7.48(1H,m), 7.57(1H,t), 7.76(1H,d), 8.02(1H,d), 8.12(1H,s) 1 H NMR (400 MHz, CDCl 3 ) 1.26 (3H, t), 1.63-1.78 (1H, m), 2.23-2.38 (2H, m), 2.41-2.49 (4H, m), 2.50-2.57 (2H, m ), 2.58-2.73 (3H, m), 2.80 (1H, d), 2.97-3.08 (1H, m), 3.42-3.53 (4H, m), 4.11-4.20 (4H, m), 4.48-4.53 (1H) , m), 7.17 (1H, d), 7.41-7.48 (1H, m), 7.57 (1H, t), 7.76 (1H, d), 8.02 (1H, d), 8.12 (1H, s)
실시예 6 :Example 6:
N-{[1-(2-(4-벤조일피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-benzoylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000030
Figure PCTKR2010003790-appb-I000030
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 100mg(0.22mmol), 탄산칼륨 120mg(0.86mmol, 4.0eq.), 벤조일 클로라이드 30mg(0.22mmol, 1.0eq.)을 사용하여 실시예 4와 동일한 방법으로 백색 고체로서의 목적 화합물 80mg(70%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 80 mg (70%) of the target compound as a white solid in the same manner as in Example 4 using 100 mg (0.22 mmol) of amide hydrochloride, 120 mg (0.86 mmol, 4.0 eq.) Of potassium carbonate, and 30 mg (0.22 mmol, 1.0 eq.) Of benzoyl chloride. ) Was obtained.
1H NMR(400MHz,CDCl3) 1.57-1.72(1H,m), 2.08-2.21(1H,m), 2.22-2.36(2H,m), 2.37-2.46(1H,m), 2.48-2.67(8H,m), 2.89(1H,t), 3.36-3.52(2H,m), 3.71-3.88(2H,m), 4.11(2H,d), 4.37-4.51(1H,m), 6.64(1H,d), 7.32-7.47(6H,m), 7.58(1H,t), 7.77(1H,d), 8.00(1H,d), 8.11(1H,s) 1 H NMR (400 MHz, CDCl 3 ) 1.57-1.72 (1H, m), 2.08-2.21 (1H, m), 2.22-2.36 (2H, m), 2.37-2.46 (1H, m), 2.48-2.67 (8H , m), 2.89 (1H, t), 3.36-3.52 (2H, m), 3.71-3.88 (2H, m), 4.11 (2H, d), 4.37-4.51 (1H, m), 6.64 (1H, d ), 7.32-7.47 (6H, m), 7.58 (1H, t), 7.77 (1H, d), 8.00 (1H, d), 8.11 (1H, s)
MS (M+1)+ 532.2MS (M + 1) + 532.2
실시예 7 :Example 7:
N-{[1-(2-(4-(2-메틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (2-Methylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide
Figure PCTKR2010003790-appb-I000031
Figure PCTKR2010003790-appb-I000031
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol) 및 탄산칼륨 60mg(0.43mmol, 4.0eq.)을 아세토니트릴 3ml에 상온에서 현탁시킨 후, o-톨루일 클로라이드 18mg(0.12mmol, 1.1eq.)을 아세토니트릴 1ml에 희석시켜 천천히 투입하였다. 가열 환류시켜 1시간 동안 교반한 후 감압농축하였다. 얻어진 잔류물에 정제수 10ml를 가한 다음 에틸 아세테이트 10ml로 2회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조시키고 감압 농축하였다. 얻어진 잔류물을 실리카겔을 이용한 크로마토그래피에 의해 정제(이동상 : 디클로로메탄/메탄올 = 5:1)하여 목적 화합물을 미백색 고체로서 42mg(71%) 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 50 mg (0.11 mmol) of amide hydrochloride and 60 mg (0.43 mmol, 4.0 eq.) Of potassium carbonate are suspended in 3 ml of acetonitrile at room temperature, and then 18 mg (0.12 mmol, 1.1 eq.) Of o-toluyl chloride is diluted in 1 ml of acetonitrile. Was added slowly. The mixture was heated to reflux, stirred for 1 hour, and then concentrated under reduced pressure. 10 ml of purified water was added to the obtained residue, followed by extraction twice with 10 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 5: 1) to give 42 mg (71%) of the target compound as an off-white solid.
1H NMR(400MHz,DMSO-d6) 1.50-1.60(1H,m), 2.00-2.10(1H,m), 2.19(3H,s), 2.22-2.55(10H,m), 2.60-2.70(2H,m), 3.07-3.11(2H,m), 3.58-3.66(2H,m), 3.84(2H,d), 4.10-4.19(1H,m), 7.11(1H,d), 7.19-7.31(3H,m), 7.72(1H,t), 7.91(1H,d), 8.11-8.18(2H,m), 8.21(1H,s), 8.99(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.50-1.60 (1H, m), 2.00-2.10 (1H, m), 2.19 (3H, s), 2.22-2.55 (10H, m), 2.60-2.70 (2H , m), 3.07-3.11 (2H, m), 3.58-3.66 (2H, m), 3.84 (2H, d), 4.10-4.19 (1H, m), 7.11 (1H, d), 7.19-7.31 (3H , m), 7.72 (1H, t), 7.91 (1H, d), 8.11-8.18 (2H, m), 8.21 (1H, s), 8.99 (1H, t)
실시예 8 :Example 8:
N-{[1-(2-(4-(3-메틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (3-methylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide
Figure PCTKR2010003790-appb-I000032
Figure PCTKR2010003790-appb-I000032
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol), 탄산칼륨 60mg(0.43mmol, 4.0eq.) 및 m-톨루일 클로라이드 18mg(0.12mmol, 1.1eq.)을 사용하여 실시예 7과 동일한 방법으로 노란색 고체로서의 목적 화합물 45mg(77%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 45 mg of the target compound as a yellow solid in the same manner as in Example 7, using 50 mg (0.11 mmol) of amide hydrochloride, 60 mg (0.43 mmol, 4.0 eq.) Of potassium carbonate and 18 mg (0.12 mmol, 1.1 eq.) Of m-toluyl chloride. (77%) was obtained.
1H NMR(400MHz,DMSO-d6) 1.08-1.18(1H,m), 1.20-1.30(1H,m), 1.50-1.60(1H,m), 2.00-2.10(1H,m), 2.32(3H,s), 2.35-2.46(8H,m), 2.58-2.68(2H,m), 3.23-3.33(2H,m), 3.52-3.62(2H,m), 3.84(2H,d), 4.10-4.20(1H,m), 7.12-7.17(2H,m), 7.22-7.32(2H,m), 7.73(1H,t), 7.91(1H,d), 8.10-8.18(2H,m), 8.21(1H,s), 8.99(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.08-1.18 (1H, m), 1.20-1.30 (1H, m), 1.50-1.60 (1H, m), 2.00-2.10 (1H, m), 2.32 (3H , s), 2.35-2.46 (8H, m), 2.58-2.68 (2H, m), 3.23-3.33 (2H, m), 3.52-3.62 (2H, m), 3.84 (2H, d), 4.10-4.20 (1H, m), 7.12-7.17 (2H, m), 7.22-7.32 (2H, m), 7.73 (1H, t), 7.91 (1H, d), 8.10-8.18 (2H, m), 8.21 (1H , s), 8.99 (1 H, t)
실시예 9 :Example 9:
N-{[1-(2-(4-(4-메틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (4-Methylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide
Figure PCTKR2010003790-appb-I000033
Figure PCTKR2010003790-appb-I000033
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol), 탄산칼륨 60mg(0.43mmol, 4.0eq.) 및 p-톨루일 클로라이드 18mg(0.12mmol, 1.1eq.)을 사용하여 실시예 7과 동일한 방법으로 미백색 고체로서의 목적 화합물 38mg(65%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 38 mg of the target compound as a white white solid in the same manner as in Example 7, using 50 mg (0.11 mmol) of amide hydrochloride, 60 mg (0.43 mmol, 4.0 eq.) Of potassium carbonate and 18 mg (0.12 mmol, 1.1 eq.) Of p-toluyl chloride. (65%) was obtained.
1H NMR(400MHz,DMSO-d6) 1.08-1.30(2H,m), 1.50-1.60(1H,m), 2.00-2.10(1H,m), 2.32(3H,s), 2.33-2.42(8H,m), 2.58-2.68(2H,m), 3.25-3.35(2H,m), 3.50-3.60(2H,m), 3.84(2H,d), 4.10-4.20(1H,m), 7.20-7.30(4H,m), 7.73(1H,t), 7.91(1H,d), 8.11-8.18(2H,m), 8.21(1H,s), 8.99(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.08-1.30 (2H, m), 1.50-1.60 (1H, m), 2.00-2.10 (1H, m), 2.32 (3H, s), 2.33-2.42 (8H , m), 2.58-2.68 (2H, m), 3.25-3.35 (2H, m), 3.50-3.60 (2H, m), 3.84 (2H, d), 4.10-4.20 (1H, m), 7.20-7.30 (4H, m), 7.73 (1H, t), 7.91 (1H, d), 8.11-8.18 (2H, m), 8.21 (1H, s), 8.99 (1H, t)
실시예 10 :Example 10
N-{[1-(2-(4-(4-플루오로벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (4-fluorobenzoyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Rommethylbenzamide
Figure PCTKR2010003790-appb-I000034
Figure PCTKR2010003790-appb-I000034
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol), 탄산칼륨 60mg(0.43mmol, 4.0eq.) 및 4-플루오로벤조일 클로라이드 19mg(0.12mmol, 1.1eq.)을 사용하여 실시예 7과 동일한 방법으로 미백색 고체로서의 목적 화합물 33mg(55%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 Target compound as an off-white solid in the same manner as Example 7 using 50 mg (0.11 mmol) of amide hydrochloride, 60 mg (0.43 mmol, 4.0 eq.) Of potassium carbonate and 19 mg (0.12 mmol, 1.1 eq.) Of 4-fluorobenzoyl chloride. 33 mg (55%) were obtained.
1H NMR(400MHz,DMSO-d6) 1.50-1.60(1H,m), 2.00-2.10(1H,m), 2.30-2.50(10H,m), 2.60-2.68(2H,m), 3.25-3.35(2H,m), 3.50-3.60(2H,m), 3.84(2H,d), 4.10-4.20(1H,m), 7.22-7.30(2H,m), 7.41-7.48(2H,m), 7.73(1H,t), 7.91(1H,d), 8.12(1H,d), 8.16(1H,d), 8.21(1H,s), 8.98(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.50-1.60 (1H, m), 2.00-2.10 (1H, m), 2.30-2.50 (10H, m), 2.60-2.68 (2H, m), 3.25-3.35 (2H, m), 3.50-3.60 (2H, m), 3.84 (2H, d), 4.10-4.20 (1H, m), 7.22-7.30 (2H, m), 7.41-7.48 (2H, m), 7.73 (1H, t), 7.91 (1H, d), 8.12 (1H, d), 8.16 (1H, d), 8.21 (1H, s), 8.98 (1H, t)
실시예 11 :Example 11:
N-{[1-(2-(4-(4-시아노벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (4-cyanobenzoyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Rommethylbenzamide
Figure PCTKR2010003790-appb-I000035
Figure PCTKR2010003790-appb-I000035
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol), 탄산칼륨 60mg(0.43mmol, 4.0eq.) 및 4-시아노벤조일 클로라이드 20mg(0.12mmol, 1.1eq.)을 사용하여 실시예 7과 동일한 방법으로 미백색 고체로서의 목적 화합물 42mg(70%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 Target compound as an off-white solid in the same manner as in Example 7, using 50 mg (0.11 mmol) of amide hydrochloride, 60 mg (0.43 mmol, 4.0 eq.) Of potassium carbonate and 20 mg (0.12 mmol, 1.1 eq.) Of 4-cyanobenzoyl chloride. 42 mg (70%) were obtained.
1H NMR(400MHz,DMSO-d6) 1.52-1.62(1H,m), 2.00-2.10(1H,m), 2.30-2.55(10H,m), 2.60-2.70(2H,m), 3.19-3.25(2H,m), 3.58-3.63(2H,m), 3.84(2H,d), 4.10-4.20(1H,m), 7.55(2H,d), 7.73(1H,t), 7.88-7.94(3H,m), 8.12-8.18(2H,m), 8.21(1H,s), 8.99(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.52-1.62 (1H, m), 2.00-2.10 (1H, m), 2.30-2.55 (10H, m), 2.60-2.70 (2H, m), 3.19-3.25 (2H, m), 3.58-3.63 (2H, m), 3.84 (2H, d), 4.10-4.20 (1H, m), 7.55 (2H, d), 7.73 (1H, t), 7.88-7.94 (3H , m), 8.12-8.18 (2H, m), 8.21 (1H, s), 8.99 (1H, t)
실시예 12 :Example 12:
N-{[1-(2-(4-(4-에틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (4-ethylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide
Figure PCTKR2010003790-appb-I000036
Figure PCTKR2010003790-appb-I000036
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol), 탄산칼륨 60mg(0.43mmol, 4.0eq.) 및 4-에틸벤조일 클로라이드 20mg(0.12mmol, 1.1eq.)을 사용하여 실시예 7과 동일한 방법으로 미백색 고체로서의 목적 화합물 48mg(79%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 48 mg of the target compound as a white white solid in the same manner as in Example 7, using 50 mg (0.11 mmol) of amide hydrochloride, 60 mg (0.43 mmol, 4.0 eq.) Of potassium carbonate and 20 mg (0.12 mmol, 1.1 eq.) Of 4-ethylbenzoyl chloride. (79%) was obtained.
1H NMR(400MHz,DMSO-d6) 1.08-1.28(5H,m), 1.50-1.60(1H,m), 2.00-2.10(1H,m), 2.32-2.47(10H,m), 2.57-2.68(4H,m), 3.50-3.60(2H,m), 3.84(2H,d), 4.10-4.19(1H,m), 7.23-7.32(4H,m), 7.73(1H,t), 7.84(1H,d), 7.91(1H,d), 8.16(1H,d), 8.21(1H,s), 8.99(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.08-1.28 (5H, m), 1.50-1.60 (1H, m), 2.00-2.10 (1H, m), 2.32-2.47 (10H, m), 2.57-2.68 (4H, m), 3.50-3.60 (2H, m), 3.84 (2H, d), 4.10-4.19 (1H, m), 7.23-7.32 (4H, m), 7.73 (1H, t), 7.84 (1H , d), 7.91 (1H, d), 8.16 (1H, d), 8.21 (1H, s), 8.99 (1H, t)
실시예 13 :Example 13:
N-{[1-(2-(4-(페닐술포닐)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (phenylsulfonyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide
Figure PCTKR2010003790-appb-I000037
Figure PCTKR2010003790-appb-I000037
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol), 탄산칼륨 60mg(0.43mmol, 4.0eq.) 및 벤젠술포닐 클로라이드 21mg(0.12mmol, 1.1eq.)을 사용하여 실시예 7과 동일한 방법으로 노란색 고체로서의 목적 화합물 34mg(55%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 34 mg of the target compound as a yellow solid in the same manner as in Example 7 using 50 mg (0.11 mmol) of amide hydrochloride, 60 mg (0.43 mmol, 4.0 eq.) Of potassium carbonate and 21 mg (0.12 mmol, 1.1 eq.) Of benzenesulfonyl chloride 55%) was obtained.
1H NMR(400MHz,DMSO-d6) 1.08-1.30(2H,m), 1.48-1.56(1H,m), 1.96-2.06(1H,m), 2.25-2.60(10H,m), 2.80-2.90(4H,m), 3.82(2H,d), 4.08-4.15(1H,m), 7.62-7.68(2H,m), 7.70-7.76(4H,m), 7.91(1H,d), 8.05-8.13(1H,m), 8.15(1H,d), 8.20(1H,s), 8.94-9.00(1H,m) 1 H NMR (400 MHz, DMSO-d 6 ) 1.08-1.30 (2H, m), 1.48-1.56 (1H, m), 1.96-2.06 (1H, m), 2.25-2.60 (10H, m), 2.80-2.90 (4H, m), 3.82 (2H, d), 4.08-4.15 (1H, m), 7.62-7.68 (2H, m), 7.70-7.76 (4H, m), 7.91 (1H, d), 8.05-8.13 (1H, m), 8.15 (1H, d), 8.20 (1H, s), 8.94-9.00 (1H, m)
실시예 14 :Example 14
N-{[1-(2-(4-프로피오닐피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-propionylpiperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000038
Figure PCTKR2010003790-appb-I000038
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol), 탄산칼륨 60mg(0.43mmol, 4.0eq.) 및 프로피오닐 클로라이드 11mg(0.12mmol, 1.1eq.)을 사용하여 실시예 7과 동일한 방법으로 노란색 고체로서의 목적 화합물 42mg(81%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 42 mg (81) of the target compound as a yellow solid in the same manner as in Example 7 using 50 mg (0.11 mmol) of amide hydrochloride, 60 mg (0.43 mmol, 4.0 eq.) Of potassium carbonate and 11 mg (0.12 mmol, 1.1 eq.) Of propionyl chloride. %) Was obtained.
1H NMR(400MHz,DMSO-d6) 0.95(3H,t), 1.50-1.60(1H,m), 2.00-2.10(1H,m), 2.25-2.40(10H,m), 2.48-2.58(2H,m), 2.58-2.68(2H,m), 3.32-3.42(4H,m), 3.84(2H,d), 4.10-4.20(1H,m), 7.73(1H,t), 7.91(1H,d), 8.12(1H,d), 8.16(1H,d), 8.21(1H,s), 8.99(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 0.95 (3H, t), 1.50-1.60 (1H, m), 2.00-2.10 (1H, m), 2.25-2.40 (10H, m), 2.48-2.58 (2H , m), 2.58-2.68 (2H, m), 3.32-3.42 (4H, m), 3.84 (2H, d), 4.10-4.20 (1H, m), 7.73 (1H, t), 7.91 (1H, d) ), 8.12 (1H, d), 8.16 (1H, d), 8.21 (1H, s), 8.99 (1H, t)
실시예 15 :Example 15:
N-{[1-(2-(4-벤질피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-benzylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000039
Figure PCTKR2010003790-appb-I000039
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.11mmol), 탄산칼륨 60mg(0.43mmol, 4.0eq.) 및 벤질 클로라이드 14mg(0.11mmol, 1.0eq.)을 사용하여 실시예 7과 동일한 방법으로 노란색 고체로서의 목적 화합물 0.042g(75%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 0.042 g (75) of the target compound as a yellow solid in the same manner as in Example 7 using 50 mg (0.11 mmol) of amide hydrochloride, 60 mg (0.43 mmol, 4.0 eq.) Of potassium carbonate and 14 mg (0.11 mmol, 1.0 eq.) Of benzyl chloride %) Was obtained.
1H NMR(400MHz,CDCl3) 1.63-1.79(1H,m), 2.26-2.39(2H,m), 2.40-2.57(10H,m), 2.61-2.77(3H,m), 2.91(1H,d), 3.08-3.14(1H,m), 3.51(2H,s), 4.08-4.17(2H,m), 4.50-4.58(1H,m), 7.23-7.35(6H,m), 7.39(1H,d), 7.58(1H,t), 7.77(1H,d), 8.03(1H,d), 8.13(1H,s) 1 H NMR (400 MHz, CDCl 3 ) 1.63-1.79 (1H, m), 2.26-2.39 (2H, m), 2.40-2.57 (10H, m), 2.61-2.77 (3H, m), 2.91 (1H, d ), 3.08-3.14 (1H, m), 3.51 (2H, s), 4.08-4.17 (2H, m), 4.50-4.58 (1H, m), 7.23-7.35 (6H, m), 7.39 (1H, d ), 7.58 (1H, t), 7.77 (1H, d), 8.03 (1H, d), 8.13 (1H, s)
실시예 16 :Example 16:
N-{[1-(1-(4-벤조일피페라진-1-일)프로판-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (1- (4-benzoylpiperazin-1-yl) propan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide
Figure PCTKR2010003790-appb-I000040
Figure PCTKR2010003790-appb-I000040
제조예 3에서 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 100mg(0.32mmol)및 제조예 10에 기술된 1-(4-벤조일피페라진-1-일)프로판-2-온 80mg(0.32mmol, 1.0eq.)을 디클로로에탄 10ml에 용해시켰다. 나트륨 트리아세톡시보로히드라이드 200mg(0.95mmol, 3.0eq.)을 가하고 상온에서 5시간 교반한 다음, 중탄산나트륨 포화 수용액 50ml를 가하고 에틸 아세테이트 30ml로 추출하였다. 유기층을 분리하여 무수 황산 마그네슘으로 건조시킨 후 실리카겔을 이용한 크로마토그래피로 정제(이동상 : 디클로로메탄/메탄올 = 25:1)하여 목적 화합물을 연노란색 고체로서 120mg(70%) 수득하였다. 100 mg (0.32 mmol) of N- (pyrrolidin- (3R) -yl-carbamoylmethyl) -3-trifluoromethylbenzamide described in Preparation Example 3 and 1- (4-benzoyl as described in Preparation Example 10 80 mg (0.32 mmol, 1.0 eq.) Of piperazin-1-yl) propan-2-one was dissolved in 10 ml of dichloroethane. 200 mg (0.95 mmol, 3.0 eq.) Of sodium triacetoxyborohydride was added thereto, stirred at room temperature for 5 hours, and then 50 ml of saturated aqueous sodium bicarbonate solution was added and extracted with 30 ml of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 25: 1) to obtain 120 mg (70%) of the title compound as a pale yellow solid.
1H NMR(400MHz,DMSO-d6) 1.00-1.09(3H,m), 1.48-1.60(1H,m), 1.96-2.10(1H,m), 2.12-2.23(1H,m), 2.24-2.55(10H,m), 2.65-2.81(2H,m), 3.53-3.66(2H,m), 3.87(2H,d), 4.07-4.17(1H,m), 7.34-7.38(2H,m), 7.42-7.48(3H,m), 7.74(1H,t), 7.92(1H,d), 8.03-8.12(1H,m), 8.17(1H,d), 8.22(1H,s), 8.93-9.03(1H,m) 1 H NMR (400 MHz, DMSO-d 6 ) 1.00-1.09 (3H, m), 1.48-1.60 (1H, m), 1.96-2.10 (1H, m), 2.12-2.23 (1H, m), 2.24-2.55 (10H, m), 2.65-2.81 (2H, m), 3.53-3.66 (2H, m), 3.87 (2H, d), 4.07-4.17 (1H, m), 7.34-7.38 (2H, m), 7.42 -7.48 (3H, m), 7.74 (1H, t), 7.92 (1H, d), 8.03-8.12 (1H, m), 8.17 (1H, d), 8.22 (1H, s), 8.93-9.03 (1H , m)
MS (M+1)+ 546.4MS (M + 1) + 546.4
실시예 17 :Example 17:
N-{[1-(3-(4-벤조일피페라진-1-일)부탄-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (3- (4-benzoylpiperazin-1-yl) butan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide
Figure PCTKR2010003790-appb-I000041
Figure PCTKR2010003790-appb-I000041
제조예 11에서 기술된 3-(4-벤조일피페라진-1-일)부탄-2-온 50mg(0.19mmol) 및 제조예 3에 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 120mg(0.38mmol, 2.0eq.)을 디클로로에탄 5ml에 용해시켰다. 나트륨 트리아세톡시보로히드라이드 200mg(0.96mmol, 5.0eq.)을 가하고 상온에서 24시간 교반한 다음, 중탄산나트륨 포화 수용액 25ml를 가하고 에틸 아세테이트 15ml로 추출하였다. 유기층을 분리하여 무수 황산 마그네슘으로 건조시킨 후 실리카겔을 이용한 크로마토그래피로 정제(이동상 : 디클로로메탄/메탄올 = 25:1)하여 목적 화합물을 연노란색 고체로서 40mg(37%) 수득하였다.50 mg (0.19 mmol) of 3- (4-benzoylpiperazin-1-yl) butan-2-one as described in Preparation Example 11 and N- (pyrrolidine- (3R) -yl-carba as described in Preparation Example 3 120 mg (0.38 mmol, 2.0 eq.) Of moylmethyl) -3-trifluoromethylbenzamide were dissolved in 5 ml of dichloroethane. 200 mg (0.96 mmol, 5.0 eq.) Of sodium triacetoxyborohydride was added thereto, stirred at room temperature for 24 hours, and then 25 ml of saturated aqueous sodium bicarbonate solution was added and extracted with 15 ml of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 25: 1) to obtain 40 mg (37%) of the title compound as a pale yellow solid.
1H NMR(400MHz,DMSO-d6) 0.92(3H,d), 0.96(3H,d), 1.48-1.62(1H,m), 1.95-2.08(1H,m), 2.31-2.48(9H,m), 2.53-2.81(3H,m), 3.48-3.67(2H,m), 3.87(2H,d), 4.08-4.17(1H,m), 7.34-7.39(2H,m), 7.43-7.48(3H,m), 7.75(1H,t), 7.93(1H,d), 7.98(1H,dd), 8.18(1H,d), 8.22(1H,s), 9.00(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 0.92 (3H, d), 0.96 (3H, d), 1.48-1.62 (1H, m), 1.95-2.08 (1H, m), 2.31-2.48 (9H, m ), 2.53-2.81 (3H, m), 3.48-3.67 (2H, m), 3.87 (2H, d), 4.08-4.17 (1H, m), 7.34-7.39 (2H, m), 7.43-7.48 (3H , m), 7.75 (1H, t), 7.93 (1H, d), 7.98 (1H, dd), 8.18 (1H, d), 8.22 (1H, s), 9.00 (1H, t)
MS (M+1)+ 560.6MS (M + 1) + 560.6
실시예 18 :Example 18:
N-{[1-(2-(4-벤조일피페라진-1-일)프로판-1-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-benzoylpiperazin-1-yl) propan-1-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide
Figure PCTKR2010003790-appb-I000042
Figure PCTKR2010003790-appb-I000042
제조예 6에서 기술된 N-{[1-(2-히드록시프로필)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 400mg(1.07mmol) 및 트리에틸아민 0.18ml(1.29mmol, 1.2eq.)을 디클로로메탄 20ml에 용해시키고 아르곤 가스하에 3℃로 냉각시켰다. 메탄술포닐 클로라이드 135mg(1.18mmol, 1.1eq.)를 천천히 반응액에 가한 다음 동일 온도에서 30분간 교반하였다. 정제수 20ml를 가한 다음 유기층을 분리하고 감압 농축하였다. 얻어진 잔류물에 아세토니트릴 10ml를 투입하여 용해시킨 다음, 탄산칼륨 444mg(3.21mmol) 및 1-벤조일피페라진 202mg(1.06mmol)을 투입하였다. 상온에서 2시간 교반한 다음, 포화 염화나트륨 수용액 15ml를 반응액에 투입하고 에틸 아세테이트 15ml로 2회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조시킨 다음 감압 농축하였다. 얻어진 잔류물을 실리카겔을 이용한 크로마토그래피에 의해 정제(이동상 : 디클로로메탄/메탄올 = 5:1 및 1:1)하여 목적 화합물을 미황색 고체로서 30mg(51%) 수득하였다.400 mg (1.07 mmol) of N-{[1- (2-hydroxypropyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide described in Preparation Example 6 And 0.18 ml (1.29 mmol, 1.2 eq.) Of triethylamine were dissolved in 20 ml of dichloromethane and cooled to 3 ° C. under argon gas. 135 mg (1.18 mmol, 1.1 eq.) Of methanesulfonyl chloride was slowly added to the reaction solution, followed by stirring at the same temperature for 30 minutes. 20 ml of purified water was added, the organic layer was separated, and concentrated under reduced pressure. 10 ml of acetonitrile was added to the obtained residue to dissolve it, and then 444 mg (3.21 mmol) of potassium carbonate and 202 mg (1.06 mmol) of 1-benzoylpiperazine were added thereto. After stirring for 2 hours at room temperature, 15 ml of saturated aqueous sodium chloride solution was added to the reaction solution, and extracted twice with 15 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 5: 1 and 1: 1) to give 30 mg (51%) of the title compound as a pale yellow solid.
1H NMR(400MHz,DMSO-d6) 1.05(3H,s), 1.55-1.65(1H,m), 2.00-2.10(1H,m), 2.15-2.25(1H,m), 2.28-2.55(9H,m), 2.70-2.85(2H,m), 3.17(1H,d), 3.54-3.65(2H,m), 3.87(2H,d), 4.10-4.20(1H,m), 7.35-7.40(2H,m), 7.40-7.47(3H,m), 7.74(1H,t), 7.92(1H,d), 8.14(1H,s), 8.18(1H,d), 8.23(1H,s), 9.01(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.05 (3H, s), 1.55-1.65 (1H, m), 2.00-2.10 (1H, m), 2.15-2.25 (1H, m), 2.28-2.55 (9H , m), 2.70-2.85 (2H, m), 3.17 (1H, d), 3.54-3.65 (2H, m), 3.87 (2H, d), 4.10-4.20 (1H, m), 7.35-7.40 (2H , m), 7.40-7.47 (3H, m), 7.74 (1H, t), 7.92 (1H, d), 8.14 (1H, s), 8.18 (1H, d), 8.23 (1H, s), 9.01 ( 1H, t)
MS (M)+ 545.6MS (M) + 545.6
실시예 19 :Example 19:
N-{[1-(1-(4-벤조일피페라진-1-일)부탄-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (1- (4- (Benzoylpiperazin-1-yl) butan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide
Figure PCTKR2010003790-appb-I000043
Figure PCTKR2010003790-appb-I000043
1-(4-벤조일피페라진-1-일)부탄-2-온 100mg(0.38mmol) 및 제조예 3에서 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 360mg (1.15mmol, 3.0eq.)을 디클로로에탄 15ml에 용해시켰다. 나트륨 트리아세톡시보로히드라이드 490mg(2.31mmol, 6.0eq.)을 가하고 상온에서 3시간 교반한 다음, 중탄산나트륨 포화 수용액 50ml를 가하고 에틸 아세테이트 50ml로 추출하였다. 유기층을 분리하여 무수 황산 마그네슘으로 건조시킨 후 실리카겔을 이용한 크로마토그래피로 정제(이동상 : 디클로로메탄/메탄올 = 25:1)하여 목적 화합물을 연노란색 고체로서 150mg(70%) 수득하였다. 100 mg (0.38 mmol) of 1- (4-benzoylpiperazin-1-yl) butan-2-one and N- (pyrrolidin- (3R) -yl-carbamoylmethyl) -3-described in Preparation Example 3 360 mg (1.15 mmol, 3.0 eq.) Of trifluoromethylbenzamide was dissolved in 15 ml of dichloroethane. 490 mg (2.31 mmol, 6.0 eq.) Of sodium triacetoxyborohydride was added thereto, stirred at room temperature for 3 hours, and then 50 ml of saturated aqueous sodium bicarbonate solution was added and extracted with 50 ml of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 25: 1) to obtain 150 mg (70%) of the title compound as a pale yellow solid.
1H NMR(400MHz,DMSO-d6) 0.84(3H,t), 1.42-1.61(3H,m), 1.98-2.08(1H,m), 2.22-2.29(1H,m), 2.30-2.52(10H,m), 2.63-2.83(2H,m), 3.53-3.67(2H,m), 3.87(2H,d), 4.08-4.19(1H,m), 7.34-7.40(2H,m), 7.42-7.48(3H,m), 7.74(1H,t), 7.92(1H,d), 8.02(1H,d), 8.18(1H,d), 8.22(1H,s), 8.99(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 0.84 (3H, t), 1.42-1.61 (3H, m), 1.98-2.08 (1H, m), 2.22-2.29 (1H, m), 2.30-2.52 (10H , m), 2.63-2.83 (2H, m), 3.53-3.67 (2H, m), 3.87 (2H, d), 4.08-4.19 (1H, m), 7.34-7.40 (2H, m), 7.42-7.48 (3H, m), 7.74 (1H, t), 7.92 (1H, d), 8.02 (1H, d), 8.18 (1H, d), 8.22 (1H, s), 8.99 (1H, t)
MS (M+1)+ 560.7MS (M + 1) + 560.7
실시예 20 :Example 20:
N-{[1-(2-(4-벤조일피페라진-1-일)부틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-benzoylpiperazin-1-yl) butyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000044
Figure PCTKR2010003790-appb-I000044
제조예 7에서 기술된 N-{[1-(2-히드록시부틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 415mg(1.07mmol)를 사용하여 실시예 18과 동일한 방법으로 노란색 고체로서의 목적 화합물 21mg(35%)을 수득하였다.415 mg (1.07 mmol) of N-{[1- (2-hydroxybutyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide as described in Preparation Example 7 To give 21 mg (35%) of the title compound as a yellow solid in the same manner as in Example 18.
1H NMR(400MHz,DMSO-d6) 0.84(3H,t), 1.40-1.52(2H,m), 1.98-2.08(1H,m), 2.22-2.30(1H,m), 2.30-2.58(10H,m), 2.65-2.86(3H,m), 3.50-3.66(2H,m), 3.87(2H,d), 4.10-4.18(1H,m), 7.34-7.48(5H,m), 7.74(1H,t), 7.92(1H,d), 8.05(1H,d), 8.18(1H,d), 8.23(1H,s), 9.90(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 0.84 (3H, t), 1.40-1.52 (2H, m), 1.98-2.08 (1H, m), 2.22-2.30 (1H, m), 2.30-2.58 (10H , m), 2.65-2.86 (3H, m), 3.50-3.66 (2H, m), 3.87 (2H, d), 4.10-4.18 (1H, m), 7.34-7.48 (5H, m), 7.74 (1H) , t), 7.92 (1H, d), 8.05 (1H, d), 8.18 (1H, d), 8.23 (1H, s), 9.90 (1H, t)
MS (M+1)+ 560.8MS (M + 1) + 560.8
실시예 21 :Example 21:
N-{[1-(2-(4-벤조일피페라진-1-일)-2-메틸프로필)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-benzoylpiperazin-1-yl) -2-methylpropyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide
Figure PCTKR2010003790-appb-I000045
Figure PCTKR2010003790-appb-I000045
제조예 8에서 기술된 N-{[1-(2-히드록시-2-메틸프로필)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 415mg(1.07mmol)를 사용하여 실시예 18과 동일한 방법으로 미황색 고체로서의 목적 화합물 27mg(45%)을 수득하였다.415 mg of N-{[1- (2-hydroxy-2-methylpropyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide described in Preparation Example 8 (1.07 mmol) of 27 mg (45%) of the title compound as a pale yellow solid were obtained in the same manner as in Example 18.
1H NMR(400MHz,DMSO-d6) 0.80-0.90(1H,m), 0.92-1.00(6H,m), 1.15-1.25(1H,m), 1.51-1.60(1H,m), 1.92-2.08(1H,m), 2.35-2.62(6H,m), 2.65-2.88(2H,m), 3.20-3.32(2H,m), 3.50-3.62(2H,m), 3.85-3.90(2H,m), 4.00-4.18(1H,m), 7.35-7.40(2H,m), 7.40-7.48(3H,m), 7.74(1H,t), 7.93(1H,d), 8.02(1H,d), 8.18(1H,d), 8.23(1H,s), 8.98-9.03(1H,m) 1 H NMR (400 MHz, DMSO-d 6 ) 0.80-0.90 (1H, m), 0.92-1.00 (6H, m), 1.15-1.25 (1H, m), 1.51-1.60 (1H, m), 1.92-2.08 (1H, m), 2.35-2.62 (6H, m), 2.65-2.88 (2H, m), 3.20-3.32 (2H, m), 3.50-3.62 (2H, m), 3.85-3.90 (2H, m) , 4.00-4.18 (1H, m), 7.35-7.40 (2H, m), 7.40-7.48 (3H, m), 7.74 (1H, t), 7.93 (1H, d), 8.02 (1H, d), 8.18 (1H, d), 8.23 (1H, s), 8.98-9.03 (1H, m)
실시예 22 :Example 22:
N-{[1-(1-(4-벤조일피페라진-1-일)-2-메틸프로판-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (1- (4-Benzoylpiperazin-1-yl) -2-methylpropan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3- Trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000046
Figure PCTKR2010003790-appb-I000046
제조예 9에서 기술된 (4-(2-히드록시-2-메틸프로필)피페라진-1-일)페닐메탄온 60mg(0.23mmol) 및 트리에틸아민 28mg(0.25mmol, 1.1eq.)을 디클로로메탄 5ml에 용해시키고 아르곤 가스하에 3℃로 냉각시켰다. 메탄술포닐 클로라이드 29mg(0.25mmol, 1.1eq.)를 천천히 반응액에 가한 다음 동일 온도에서 1.5시간 교반하였다. 정제수 5ml를 가한 다음 유기층을 분리하고 감압 농축하였다. 얻어진 잔류물에 아세토니트릴 5ml를 투입하여 용해시킨 다음, 탄산칼륨 76mg(0.55mmol) 및 제조예 3에 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 58mg(0.18mmol)을 투입하였다. 상온에서 3시간 교반한 다음, 포화 염화나트륨 수용액 10ml를 반응액에 투입하고 에틸 아세테이트 10ml로 2회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조시킨 다음 감압 농축하였다. 얻어진 잔류물을 실리카겔을 이용한 크로마토그래피에 의해 정제(이동상 : 디클로로메탄/메탄올 = 5:1 및 1:1)하여 목적 화합물을 미황색 고체로서 57mg(45%) 수득하였다.60 mg (0.23 mmol) and 28 mg (0.25 mmol, 1.1 eq.) Of (4- (2-hydroxy-2-methylpropyl) piperazin-1-yl) phenylmethanone described in Preparation Example 9 were diluted with It was dissolved in 5 ml of methane and cooled to 3 ° C. under argon gas. 29 mg (0.25 mmol, 1.1 eq.) Of methanesulfonyl chloride was slowly added to the reaction solution, followed by stirring at the same temperature for 1.5 hours. 5 ml of purified water was added, the organic layer was separated, and concentrated under reduced pressure. 5 ml of acetonitrile was added to the obtained residue to dissolve it, and then 76 mg (0.55 mmol) of potassium carbonate and N- (pyrrolidin- (3R) -yl-carbamoylmethyl) -3-trifluoro described in Preparation Example 3 58 mg (0.18 mmol) of chloromethylbenzamide was added thereto. After stirring for 3 hours at room temperature, 10 ml of saturated aqueous sodium chloride solution was added to the reaction solution, and extracted twice with 10 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 5: 1 and 1: 1) to give 57 mg (45%) of the title compound as a pale yellow solid.
1H NMR(400MHz,DMSO-d6) 0.92-1.00(6H,m), 1.50-1.60(1H,m), 1.92-2.08(1H,m), 2.30-2.60(8H,m), 2.64-2.78(1H,m), 2.80-2.88(1H,m), 3.30-3.62(4H,m), 3.83-3.90(2H,m), 4.05-4.18(1H,m), 7.35-7.40(2H,m), 7.40-7.47(3H,m), 7.74(1H,t), 7.92(1H,d), 8.04(1H,d), 8.18(1H,d), 8.23(1H,s), 9.06-9.13(1H,m) 1 H NMR (400 MHz, DMSO-d 6 ) 0.92-1.00 (6H, m), 1.50-1.60 (1H, m), 1.92-2.08 (1H, m), 2.30-2.60 (8H, m), 2.64-2.78 (1H, m), 2.80-2.88 (1H, m), 3.30-3.62 (4H, m), 3.83-3.90 (2H, m), 4.05-4.18 (1H, m), 7.35-7.40 (2H, m) , 7.40-7.47 (3H, m), 7.74 (1H, t), 7.92 (1H, d), 8.04 (1H, d), 8.18 (1H, d), 8.23 (1H, s), 9.06-9.13 (1H , m)
실시예 23 :Example 23:
N-{[1-(3-(4-(3-클로로페닐)피페라진-1-일)부탄-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (3- (4- (3-chlorophenyl) piperazin-1-yl) butan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000047
Figure PCTKR2010003790-appb-I000047
3-(4-(3-클로로페닐)피페라진-1-일)부탄-2-온 100mg(0.37mmol) 및 제조예 3에서 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 240mg(0.75mmol, 2.0eq.)을 디클로로에탄 10ml에 용해시켰다. 나트륨 트리아세톡시보로히드라이드 480mg(2.25mmol, 6.0eq.)을 가하고 상온에서 7시간 교반한 다음, 중탄산나트륨 포화 수용액 30ml를 가하고 에틸 아세테이트 20ml로 추출하였다. 유기층을 분리하여 무수 황산 마그네슘으로 건조시킨 후 실리카겔을 이용한 크로마토그래피로 정제(이동상 : 디클로로메탄/메탄올 = 25:1)하여 목적 화합물을 백색 고체로서 140mg(66%) 수득하였다. 100 mg (0.37 mmol) of 3- (4- (3-chlorophenyl) piperazin-1-yl) butan-2-one and N- (pyrrolidin- (3R) -yl-carbamoyl described in Preparation Example 3 240 mg (0.75 mmol, 2.0 eq.) Of methyl) -3-trifluoromethylbenzamide were dissolved in 10 ml of dichloroethane. 480 mg (2.25 mmol, 6.0 eq.) Of sodium triacetoxyborohydride was added thereto, stirred at room temperature for 7 hours, and then 30 ml of saturated aqueous sodium bicarbonate solution was added and extracted with 20 ml of ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 25: 1) to obtain 140 mg (66%) of the title compound as a white solid.
1H NMR(400MHz,DMSO-d6) 0.91-1.05(6H,m), 1.48-1.64(1H,m), 1.97-2.19(1H,m), 2.32-2.41(1H,m), 2.53-2.85(9H,m), 3.05-3.20(4H,m), 3.87(2H,d), 4.07-4.20(1H,m), 6.76(1H,d), 6.87(1H,d), 6.91(1H,s), 7.19(1H,t), 7.74(1H,t), 7.93(1H,d), 7.97-8.03(1H,m), 8.18(1H,d), 8.23(1H,s), 9.02(1H,s) 1 H NMR (400 MHz, DMSO-d 6 ) 0.91-1.05 (6H, m), 1.48-1.64 (1H, m), 1.97-2.19 (1H, m), 2.32-2.41 (1H, m), 2.53-2.85 (9H, m), 3.05-3.20 (4H, m), 3.87 (2H, d), 4.07-4.20 (1H, m), 6.76 (1H, d), 6.87 (1H, d), 6.91 (1H, s ), 7.19 (1H, t), 7.74 (1H, t), 7.93 (1H, d), 7.97-8.03 (1H, m), 8.18 (1H, d), 8.23 (1H, s), 9.02 (1H, s)
실시예 24 :Example 24:
N-{[1-(1-(4-페닐피페라진-1-일)프로판-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (1- (1- (4-phenylpiperazin-1-yl) propan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide
Figure PCTKR2010003790-appb-I000048
Figure PCTKR2010003790-appb-I000048
1-(4-페닐피페라진-1-일)프로판-2-온 100mg(0.46mmol), 제조예 3에서 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 290mg(0.92mmol, 2.0eq.), 나트륨 트리아세톡시보로히드라이드 580mg(2.75mmol, 6.0eq.)을 사용하여 실시예 23과 동일한 방법으로 백색 고체로서의 목적 화합물 130mg(55%)을 수득하였다.100 mg (0.46 mmol) of 1- (4-phenylpiperazin-1-yl) propan-2-one, N- (pyrrolidin- (3R) -yl-carbamoylmethyl) -3- as described in Preparation Example 3 130 mg (55) of the target compound as a white solid in the same manner as in Example 23 using 290 mg (0.92 mmol, 2.0 eq.) Of trifluoromethylbenzamide and 580 mg (2.75 mmol, 6.0 eq.) Of sodium triacetoxyborohydride. %) Was obtained.
1H NMR(400MHz,DMSO-d6) 1.06(3H,t), 1.53-1.62(1H,m), 2.00-2.09(1H,m), 2.17-2.25(1H,m), 2.41-2.62(8H,m), 2.70-2.83(2H,m), 3.07-3.15(4H,m), 3.87(2H,d), 4.10-4.20(1H,m), 6.77(1H,t), 6.91(2H,d), 7.20(2H,t), 7.74(1H,t), 7.93(1H,d), 8.09(1H,d), 8.18(1H,d), 8.23(1H,s), 8.98(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.06 (3H, t), 1.53-1.62 (1H, m), 2.00-2.09 (1H, m), 2.17-2.25 (1H, m), 2.41-2.62 (8H , m), 2.70-2.83 (2H, m), 3.07-3.15 (4H, m), 3.87 (2H, d), 4.10-4.20 (1H, m), 6.77 (1H, t), 6.91 (2H, d ), 7.20 (2H, t), 7.74 (1H, t), 7.93 (1H, d), 8.09 (1H, d), 8.18 (1H, d), 8.23 (1H, s), 8.98 (1H, t)
실시예 25 :Example 25
N-{[1-(1-(4-시클로헥실피페라진-1-일)프로판-2-일)-피롤리딘(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (1- (4- (cyclohexylpiperazin-1-yl) propan-2-yl) -pyrrolidin (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide
Figure PCTKR2010003790-appb-I000049
Figure PCTKR2010003790-appb-I000049
1-(4-시클로헥실피페라진-1-일)프로판-2-온 100mg(0.45mmol), 제조예 3에서 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 280mg (0.89mmol, 2.0eq.), 나트륨 트리아세톡시보로히드라이드 570mg(2.67mmol, 6.0eq.)을 사용하여 실시예 23과 동일한 방법으로 백색 고체로서의 목적 화합물 100mg(43%)을 수득하였다.100 mg (0.45 mmol) of 1- (4-cyclohexylpiperazin-1-yl) propan-2-one, N- (pyrrolidin- (3R) -yl-carbamoylmethyl)-described in Preparation Example 3 100 mg of the desired compound as a white solid in the same manner as in Example 23 using 280 mg (0.89 mmol, 2.0 eq.) Of 3-trifluoromethylbenzamide, 570 mg (2.67 mmol, 6.0 eq.) Of sodium triacetoxyborohydride (43%) was obtained.
1H NMR(400MHz,DMSO-d6) 1.00(3H,t), 1.03-1.21(6H,m), 1.50-1.61(2H,m), 1.68-1.79(4H,m), 2.01-2.05(1H,m), 2.06-2.12(1H,m), 2.13-2.19(1H,m), 2.30-2.41(4H,m), 2.42-2.51(7H,m), 2.65-2.82(2H,m), 3.87(2H,d), 4.08-4.17(1H,m), 7.74(1H,t), 7.93(1H,d), 8.06(1H,d), 8.18(1H,d), 8.23(1H,s), 8.97(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.00 (3H, t), 1.03-1.21 (6H, m), 1.50-1.61 (2H, m), 1.68-1.79 (4H, m), 2.01-2.05 (1H , m), 2.06-2.12 (1H, m), 2.13-2.19 (1H, m), 2.30-2.41 (4H, m), 2.42-2.51 (7H, m), 2.65-2.82 (2H, m), 3.87 (2H, d), 4.08-4.17 (1H, m), 7.74 (1H, t), 7.93 (1H, d), 8.06 (1H, d), 8.18 (1H, d), 8.23 (1H, s), 8.97 (1H, t)
실시예 26 :Example 26:
N-{[1-(2-(4-(2-히드록시부틸)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (2-hydroxybutyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Rommethylbenzamide
Figure PCTKR2010003790-appb-I000050
Figure PCTKR2010003790-appb-I000050
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 100mg(0.19mmol) 및 탄산칼륨 129mg(0.93mmol, 5.0eq.)을 아세토니트릴 3ml에 현탁시켰다. 2-에틸옥시란 13mg(0.19mmol)을 가하고 80℃에서 일야 환류, 교반한 뒤 실온으로 냉각시켰다. 정제수 15ml를 가한 다음 에틸 아세테이트 15ml로 3회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조, 감압 농축하였다. 얻어진 잔류물을 실리카겔을 이용한 크로마토그래피로 정제(이동상 : 디클로로메탄/메탄올 = 1:1)하여 백색 고체로서의 목적 화합물 73mg(78%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 100 mg (0.19 mmol) of amide hydrochloride and 129 mg (0.93 mmol, 5.0 eq.) Of potassium carbonate were suspended in 3 ml of acetonitrile. 13 mg (0.19 mmol) of 2-ethyloxirane was added thereto, and the mixture was stirred and refluxed at 80 ° C. overnight, followed by cooling to room temperature. 15 ml of purified water was added, followed by extraction three times with 15 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 1: 1) to give 73 mg (78%) of the title compound as a white solid.
MS (M+1)+ 500.6MS (M + 1) + 500.6
실시예 27 :Example 27:
N-{[1-(2-(4-(2-히드록시-2-메틸프로필)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (2-hydroxy-2-methylpropyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl}- 3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000051
Figure PCTKR2010003790-appb-I000051
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 100mg(0.19mmol), 탄산칼륨 129mg(0.93mmol, 5.0eq.) 및 2,2-디메틸옥시란 13mg(0.19mmol)을 사용하여 실시예 26과 동일한 방법으로 백색 고체로서의 목적 화합물 62mg(67%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 62 mg (67) of the target compound as a white solid in the same manner as in Example 26 using 100 mg (0.19 mmol) of amide hydrochloride, 129 mg (0.93 mmol, 5.0 eq.) Of potassium carbonate and 13 mg (0.19 mmol) of 2,2-dimethyloxirane. %) Was obtained.
MS (M+1)+ 500.6MS (M + 1) + 500.6
실시예 28 :Example 28:
N-{[1-(2-(4-(2-히드록시-2-페닐에틸)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (2-hydroxy-2-phenylethyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl}- 3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000052
Figure PCTKR2010003790-appb-I000052
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 100mg(0.19mmol), 탄산칼륨 129mg(0.93mmol, 5.0eq.) 및 2-페닐옥시란 22mg(0.19mmol)을 사용하여 실시예 26과 동일한 방법으로 노란색 고체로서의 목적 화합물 63mg(62%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 63 mg (62%) of the target compound as a yellow solid in the same manner as in Example 26 using 100 mg (0.19 mmol) of amide hydrochloride, 129 mg (0.93 mmol, 5.0 eq.) Of potassium carbonate and 22 mg (0.19 mmol) of 2-phenyloxirane. Obtained.
MS (M+1)+ 548.3MS (M + 1) + 548.3
실시예 29 :Example 29:
N-{[1-(2-(4-(2-(4-클로로페닐)-2-히드록시에틸)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (2- (4-chlorophenyl) -2-hydroxyethyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl ] -Methyl} -3-trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000053
Figure PCTKR2010003790-appb-I000053
제조예 5에서 기술된 N-{[1-(2-(피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 100mg(0.19mmol), 탄산칼륨 129mg(0.93mmol, 5.0eq.) 및 2-(4-클로로페닐)옥시란 23mg(0.19mmol)을 사용하여 실시예 26과 동일한 방법으로 백색 고체로서의 목적 화합물 77mg(71%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenz described in Preparation Example 5 Target compound as a white solid in the same manner as in Example 26, using 100 mg (0.19 mmol) of amide hydrochloride, 129 mg (0.93 mmol, 5.0 eq.) Of potassium carbonate and 23 mg (0.19 mmol) of 2- (4-chlorophenyl) oxirane 77 mg (71%) were obtained.
MS (M)+ 582.3MS (M) + 582.3
실시예 30 :Example 30:
N-{[1-(2-(4-벤조일피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-benzoylpiperazin-1-yl) -2-oxoethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide
Figure PCTKR2010003790-appb-I000054
Figure PCTKR2010003790-appb-I000054
제조예 14에서 기술된 N-{[1-(2-(피페라진-1-일)-2-옥소-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 100mg(0.21mmol) 및 탄산칼륨 120mg(0.83mmol, 4.0eq.)을 아세토니트릴 10ml에 상온에서 현탁시킨 후, 벤조일 클로라이드 30mg(0.21mmol, 1.0eq.)을 아세토니트릴 1ml에 희석시켜 천천히 투입하였다. 가열 환류시켜 1시간 동안 교반한 후 감압 농축하였다. 얻어진 잔류물에 정제수 10ml를 가한 다음 에틸 아세테이트 10ml로 2회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조시키고 감압 농축하였다. 얻어진 잔류물을 실리카겔을 이용한 크로마토그래피에 의해 정제(이동상 : 디클로로메탄/메탄올 = 25:1)하여 목적 화합물을 백색 고체로서 70mg(61%) 수득하였다.N-{[1- (2- (piperazin-1-yl) -2-oxo-ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3- as described in Preparation Example 14 100 mg (0.21 mmol) of trifluoromethylbenzamide hydrochloride and 120 mg (0.83 mmol, 4.0 eq.) Of potassium carbonate were suspended in 10 ml of acetonitrile at room temperature, followed by 30 mg (0.21 mmol, 1.0 eq.) Of benzoyl chloride in 1 ml of acetonitrile. Diluted in and added slowly. The mixture was heated to reflux, stirred for 1 hour, and then concentrated under reduced pressure. 10 ml of purified water was added to the obtained residue, followed by extraction twice with 10 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 25: 1) to give 70 mg (61%) of the target compound as a white solid.
1H NMR(400MHz,DMSO-d6) 1.53-1.68(1H,m), 2.01-2.11(1H,m), 2.37-2.48(2H,m), 2.66(1H,d), 2.73(1H,t), 3.42-3.68(10H,m), 3.84(2H,d), 4.10-4.21(1H,m), 7.38-7.41(2H,m), 7.42-7.48(3H,m), 7.72(1H,t), 7.91(1H,t), 8.12(1H,d), 8.16(1H,d), 8.21(1H,s), 8.99(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.53-1.68 (1H, m), 2.01-2.11 (1H, m), 2.37-2.48 (2H, m), 2.66 (1H, d), 2.73 (1H, t ), 3.42-3.68 (10H, m), 3.84 (2H, d), 4.10-4.21 (1H, m), 7.38-7.41 (2H, m), 7.42-7.48 (3H, m), 7.72 (1H, t) ), 7.91 (1H, t), 8.12 (1H, d), 8.16 (1H, d), 8.21 (1H, s), 8.99 (1H, t)
MS (M+1)+ 546.2MS (M + 1) + 546.2
실시예 31 :Example 31:
N-{[1-(2-(4-(4-메틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (4-Methylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000055
Figure PCTKR2010003790-appb-I000055
제조예 14에서 기술된 N-{[1-(2-(피페라진-1-일)-2-옥소-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.10mmol) 및 탄산칼륨 60mg(0.42mmol, 4.0eq.), 4-메틸벤조일 클로라이드 20mg(0.10mmol, 1.0eq.)을 사용하여 실시예 30과 동일한 방법으로 백색 고체로서의 목적 화합물 20mg(34%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) -2-oxo-ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3- as described in Preparation Example 14 White in the same manner as in Example 30, using 50 mg (0.10 mmol) of trifluoromethylbenzamide hydrochloride, 60 mg (0.42 mmol, 4.0 eq.) Of potassium carbonate, 20 mg (0.10 mmol, 1.0 eq.) Of 4-methylbenzoyl chloride. 20 mg (34%) of the title compound as a solid were obtained.
1H NMR(400MHz,DMSO-d6) 1.18(3H,t), 1.53-1.66(1H,m), 2.01-2.13(1H,m), 2.38-2.47(2H,m), 2.58-2.78(4H,m), 3.38-3.47(4H,m), 3.48-3.62(4H,m), 3.84(2H,d), 4.09-4.21(1H,m), 7.26(2H,d), 7.32(2H,d), 7.72(1H,t), 7.90(1H,d), 8.11(1H,d), 8.13(1H,d), 8.21(1H,s), 8.99(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.18 (3H, t), 1.53-1.66 (1H, m), 2.01-2.13 (1H, m), 2.38-2.47 (2H, m), 2.58-2.78 (4H , m), 3.38-3.47 (4H, m), 3.48-3.62 (4H, m), 3.84 (2H, d), 4.09-4.21 (1H, m), 7.26 (2H, d), 7.32 (2H, d) ), 7.72 (1H, t), 7.90 (1H, d), 8.11 (1H, d), 8.13 (1H, d), 8.21 (1H, s), 8.99 (1H, t)
실시예 32 :Example 32:
N-{[1-(2-(4-(4-에틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (4-ethylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000056
Figure PCTKR2010003790-appb-I000056
제조예 14에서 기술된 N-{[1-(2-(피페라진-1-일)-2-옥소-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.10mmol) 및 탄산칼륨 60mg(0.42mmol, 4.0eq.), 4-에틸벤조일 클로라이드 20mg(0.10mmol, 1.0eq.)을 사용하여 실시예 30과 동일한 방법으로 백색 고체로서의 목적 화합물 20mg(33%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) -2-oxo-ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3- as described in Preparation Example 14 White in the same manner as in Example 30, using 50 mg (0.10 mmol) of trifluoromethylbenzamide hydrochloride, 60 mg (0.42 mmol, 4.0 eq.) Of potassium carbonate, 20 mg (0.10 mmol, 1.0 eq.) Of 4-ethylbenzoyl chloride. 20 mg (33%) of the title compound as a solid were obtained.
1H NMR(400MHz,DMSO-d6) 1.18(3H,t), 1.53-1.65(1H,m), 2.01-2.12(1H,m), 2.37-2.48(2H,m), 2.57-2.78(4H,m), 3.25-3.35(2H,m), 3.38-3.47(4H,m), 3.48-3.65(4H,m), 3.84(2H,d), 4.11-4.22(1H,m), 7.26(2H,d), 7.32(2H,d), 7.72(1H,t), 7.90(1H,d), 8.11(1H,d), 8.16(1H,d), 8.21(1H,s), 8.99(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.18 (3H, t), 1.53-1.65 (1H, m), 2.01-2.12 (1H, m), 2.37-2.48 (2H, m), 2.57-2.78 (4H , m), 3.25-3.35 (2H, m), 3.38-3.47 (4H, m), 3.48-3.65 (4H, m), 3.84 (2H, d), 4.11-4.22 (1H, m), 7.26 (2H) , d), 7.32 (2H, d), 7.72 (1H, t), 7.90 (1H, d), 8.11 (1H, d), 8.16 (1H, d), 8.21 (1H, s), 8.99 (1H, t)
실시예 33 :Example 33:
N-{[1-(2-(4-(3-메틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (3-Methylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000057
Figure PCTKR2010003790-appb-I000057
제조예 14에서 기술된 N-{[1-(2-(피페라진-1-일)-2-옥소-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.10mmol) 및 탄산칼륨 60mg(0.42mmol, 4.0eq.), 3-메틸벤조일 클로라이드 20mg(0.10mmol, 1.0eq.)을 사용하여 실시예 30과 동일한 방법으로 백색 고체로서의 목적 화합물 25mg(43%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) -2-oxo-ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3- as described in Preparation Example 14 White in the same manner as in Example 30, using 50 mg (0.10 mmol) of trifluoromethylbenzamide hydrochloride, 60 mg (0.42 mmol, 4.0 eq.) Of potassium carbonate, 20 mg (0.10 mmol, 1.0 eq.) Of 3-methylbenzoyl chloride 25 mg (43%) of the title compound as a solid were obtained.
1H NMR(400MHz,DMSO-d6) 1.62-1.75(1H,m), 2.05-2.18(1H,m), 2.34(3H,s), 2.54-2.64(2H,m), 2.68-2.97(4H,m), 3.42-3.80(8H,m), 3.87(2H,d), 4.16-4.28(1H,m), 7.20(1H,d), 7.23(1H,s), 7.27(1H,d), 7.34(1H,t), 7.74(1H,t), 7.92(1H,d), 8.18(2H,d), 8.23(1H,s), 9.04(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.62-1.75 (1H, m), 2.05-2.18 (1H, m), 2.34 (3H, s), 2.54-2.64 (2H, m), 2.68-2.97 (4H , m), 3.42-3.80 (8H, m), 3.87 (2H, d), 4.16-4.28 (1H, m), 7.20 (1H, d), 7.23 (1H, s), 7.27 (1H, d), 7.34 (1H, t), 7.74 (1H, t), 7.92 (1H, d), 8.18 (2H, d), 8.23 (1H, s), 9.04 (1H, t)
실시예 34 :Example 34:
N-{[1-(2-(4-(2-메틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (2-Methylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000058
Figure PCTKR2010003790-appb-I000058
제조예 14에서 기술된 N-{[1-(2-(피페라진-1-일)-2-옥소-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 염산염 50mg(0.10mmol) 및 탄산칼륨 60mg(0.42mmol, 4.0eq.), 2-메틸벤조일 클로라이드 20mg(0.10mmol, 1.0eq.)을 사용하여 실시예 30과 동일한 방법으로 백색 고체로서의 목적 화합물 20mg(34%)을 수득하였다.N-{[1- (2- (piperazin-1-yl) -2-oxo-ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3- as described in Preparation Example 14 White in the same manner as in Example 30, using 50 mg (0.10 mmol) of trifluoromethylbenzamide hydrochloride, 60 mg (0.42 mmol, 4.0 eq.) Of potassium carbonate, 20 mg (0.10 mmol, 1.0 eq.) Of 2-methylbenzoyl chloride. 20 mg (34%) of the title compound as a solid were obtained.
1H NMR(400MHz,DMSO-d6) 1.62-1.82(1H,m), 2.05-2.20(1H,m), 2.22(3H,s), 2.70-3.00(6H,m), 3.17-3.22(3H,m), 3.52-3.78(5H,m), 3.87-3.93(2H,m), 4.16-4.32(1H,m), 7.20-7.38(4H,m), 7.74(1H,t), 7.93(1H,t), 8.18(1H,d), 8.23(1H,s), 8.24-8.32(1H,m), 9.02-9.09(1H,m) 1 H NMR (400 MHz, DMSO-d 6 ) 1.62-1.82 (1H, m), 2.05-2.20 (1H, m), 2.22 (3H, s), 2.70-3.00 (6H, m), 3.17-3.22 (3H , m), 3.52-3.78 (5H, m), 3.87-3.93 (2H, m), 4.16-4.32 (1H, m), 7.20-7.38 (4H, m), 7.74 (1H, t), 7.93 (1H) , t), 8.18 (1H, d), 8.23 (1H, s), 8.24-8.32 (1H, m), 9.02-9.09 (1H, m)
실시예 35 :Example 35:
N-{[1-(2-(4-페닐피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-phenylpiperazin-1-yl) -2-oxoethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide
Figure PCTKR2010003790-appb-I000059
Figure PCTKR2010003790-appb-I000059
제조예 3에서 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 50mg(0.16mmol) 및 탄산칼륨 90mg(0.63mmol, 4.0eq.), 2-클로로-1-(4-페닐피페라진-1-일)에탄온 40mg(0.16mmol, 1.0eq.)을 사용하여 실시예 30과 동일한 방법으로 백색 고체로서의 목적 화합물 40mg(49%)을 수득하였다.50 mg (0.16 mmol) of N- (pyrrolidin- (3R) -yl-carbamoylmethyl) -3-trifluoromethylbenzamide and 90 mg (0.63 mmol, 4.0 eq.) Of potassium carbonate described in Preparation Example 3, 40 mg (49%) of the target compound as a white solid were obtained by the same method as Example 30, using 40 mg (0.16 mmol, 1.0 eq.) Of 2-chloro-1- (4-phenylpiperazin-1-yl) ethanone. It was.
1H NMR(400MHz,DMSO-d6) 1.57-1.68(1H,m), 2.01-2.11(1H,m), 2.37-2.48(2H,m), 2.62-2.71(1H,m), 2.78(1H,t), 3.01-3.16(4H,m), 3.27-3.32(2H,m), 3.46-3.56(2H,m), 3.58-3.67(2H,m), 3.85(2H,d), 4.11-4.22(1H,m), 6.79(1H,t), 6.93(2H,d), 7.21(2H,t), 7.72(1H,t), 7.91(1H,d), 8.16-8.18(2H,m), 8.21(1H,s), 8.98-9.03(1H,m) 1 H NMR (400 MHz, DMSO-d 6 ) 1.57-1.68 (1H, m), 2.01-2.11 (1H, m), 2.37-2.48 (2H, m), 2.62-2.71 (1H, m), 2.78 (1H , t), 3.01-3.16 (4H, m), 3.27-3.32 (2H, m), 3.46-3.56 (2H, m), 3.58-3.67 (2H, m), 3.85 (2H, d), 4.11-4.22 (1H, m), 6.79 (1H, t), 6.93 (2H, d), 7.21 (2H, t), 7.72 (1H, t), 7.91 (1H, d), 8.16-8.18 (2H, m), 8.21 (1H, s), 8.98-9.03 (1H, m)
실시예 36 :Example 36:
N-{[1-(2-(4-(벤족시카르보닐)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4- (Benzooxycarbonyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide
Figure PCTKR2010003790-appb-I000060
Figure PCTKR2010003790-appb-I000060
제조예 3에서 기술된 N-(피롤리딘-(3R)-일-카바모일메틸)-3-트리플루오로메틸벤즈아미드 50mg(0.16mmol) 및 탄산칼륨 90mg(0.63mmol, 4.0eq.), 벤질 4-(2-클로로아세틸)피페라진-1-카복실레이트 30mg(0.16mmol, 1.0eq.)을 사용하여 실시예 30과 동일한 방법으로 백색 고체로서의 목적 화합물 40mg(44%)을 수득하였다.50 mg (0.16 mmol) of N- (pyrrolidin- (3R) -yl-carbamoylmethyl) -3-trifluoromethylbenzamide and 90 mg (0.63 mmol, 4.0 eq.) Of potassium carbonate described in Preparation Example 3, 40 mg (44%) of the target compound as a white solid were obtained by the same method as Example 30 using 30 mg (0.16 mmol, 1.0 eq.) Of benzyl 4- (2-chloroacetyl) piperazine-1-carboxylate.
1H NMR(400MHz,DMSO-d6) 1.54-1.65(1H,m), 2.01-2.10(1H,m), 2.38-2.43(1H,m), 2.44-2.47(1H,m), 2.62-2.70(1H,m), 2.73(1H,t), 3.26-3.34(4H,m), 3.38-3.45(4H,m), 3.46-3.53(2H,m), 3.85(2H,d), 4.12-4.18(1H,m), 5.08(2H,s), 7.28-7.37(5H,m), 7.72(1H,t), 7.90(1H,d), 8.13(1H,d), 8.16(1H,d), 8.22(1H,s), 9.01(1H,t) 1 H NMR (400 MHz, DMSO-d 6 ) 1.54-1.65 (1H, m), 2.01-2.10 (1H, m), 2.38-2.43 (1H, m), 2.44-2.47 (1H, m), 2.62-2.70 (1H, m), 2.73 (1H, t), 3.26-3.34 (4H, m), 3.38-3.45 (4H, m), 3.46-3.53 (2H, m), 3.85 (2H, d), 4.12-4.18 (1H, m), 5.08 (2H, s), 7.28-7.37 (5H, m), 7.72 (1H, t), 7.90 (1H, d), 8.13 (1H, d), 8.16 (1H, d), 8.22 (1H, s), 9.01 (1H, t)
실시예 37 :Example 37:
N-{[1-(2-(4-벤조일-2,5-디메틸피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-benzoyl-2,5-dimethylpiperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Rommethylbenzamide
Figure PCTKR2010003790-appb-I000061
Figure PCTKR2010003790-appb-I000061
N-{[1-(2-히드록시에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드 200mg(0.56mmol) 및 트리에틸아민 68mg(0.69mmol, 1.2eq.)을 디클로로메탄 10ml에 용해시키고 아르곤 가스하에 3℃로 냉각시켰다. 메탄술포닐 클로라이드 70mg(0.61mmol, 1.1eq.)를 천천히 반응액에 가한 다음 동일 온도에서 1시간 교반하였다. 정제수 10ml를 가한 다음 유기층을 분리하고 감압 농축하였다. 얻어진 잔류물에 아세토니트릴 10ml를 투입하여 용해시킨 다음, 탄산칼륨 247mg(1.78mmol) 및 1-벤조일-2,5-디메틸피페라진 염산염 114mg(0.45mmol)을 투입하였다. 상온에서 4시간 교반한 다음, 포화 염화나트륨 수용액 20ml를 반응액에 투입하고 에틸 아세테이트 20ml로 2회 추출하였다. 유기층을 모아 무수 황산 마그네슘으로 건조시킨 다음 감압 농축하였다. 얻어진 잔류물을 실리카겔을 이용한 크로마토그래피에 의해 정제(이동상 : 디클로로메탄/메탄올 = 5:1 및 1:1)하여 목적 화합물을 미황색 고체로서 159mg(51%) 수득하였다.200 mg (0.56 mmol) of N-{[1- (2-hydroxyethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide and 68 mg of triethylamine 0.69 mmol, 1.2 eq.) Was dissolved in 10 ml of dichloromethane and cooled to 3 ° C. under argon gas. 70 mg (0.61 mmol, 1.1 eq.) Of methanesulfonyl chloride was slowly added to the reaction solution, followed by stirring at the same temperature for 1 hour. 10 ml of purified water was added, the organic layer was separated, and concentrated under reduced pressure. 10 ml of acetonitrile was added to the residue to dissolve it, and then 247 mg (1.78 mmol) of potassium carbonate and 114 mg (0.45 mmol) of 1-benzoyl-2,5-dimethylpiperazine hydrochloride were added thereto. After stirring for 4 hours at room temperature, 20 ml of saturated aqueous sodium chloride solution was added to the reaction solution, and extracted twice with 20 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by chromatography on silica gel (mobile phase: dichloromethane / methanol = 5: 1 and 1: 1) to give 159 mg (51%) of the title compound as a pale yellow solid.
MS (M+1)+ 560.4MS (M + 1) + 560.4
이상에서는 본 발명의 바람직한 실시예에 대해서 설명하였으나, 본 발명은 상술한 특정의 실시예에 한정되지 아니하며, 당해 기술분야에서 통상의 지식을 가진 자라면 본원 발명의 요지를 벗어남이 없이 다양한 변형 실시가 가능함은 물론이다. 따라서, 본 발명의 범위는 위의 실시예에 국한해서 해석되어서는 안되며, 후술하는 특허청구범위 뿐만 아니라 이 특허청구범위와 균등한 것들에 의해 정해져야 할 것이다.In the above description of the preferred embodiment of the present invention, the present invention is not limited to the specific embodiments described above, those skilled in the art various modifications without departing from the gist of the present invention Of course it is possible. Therefore, the scope of the present invention should not be construed as being limited to the above embodiments, but should be defined by the claims below and equivalents thereof.

Claims (6)

  1. 하기 화학식 1의 화합물: A compound of formula
    [화학식 1][Formula 1]
    Figure PCTKR2010003790-appb-I000062
    Figure PCTKR2010003790-appb-I000062
    상기 화학식 1에서,In Chemical Formula 1,
    R1는 독립적으로 수소 원자, C1 - C3 알킬, 페닐, 벤질, 벤조일, 벤젠술포닐, C1 - C3 알킬카르보닐, C3 - C7 시클로알킬, R 1 is independently a hydrogen atom, C 1 -C 3 alkyl, phenyl, benzyl, benzoyl, benzenesulfonyl, C 1 -C 3 alkylcarbonyl, C 3 -C 7 cycloalkyl,
    [화학식 2][Formula 2]
    Figure PCTKR2010003790-appb-I000063
    Figure PCTKR2010003790-appb-I000063
    [화학식 3][Formula 3]
    Figure PCTKR2010003790-appb-I000064
    , 및
    Figure PCTKR2010003790-appb-I000064
    , And
    [화학식 4][Formula 4]
    Figure PCTKR2010003790-appb-I000065
    Figure PCTKR2010003790-appb-I000065
    로 이루어진 군에서 선택될 수 있고; It may be selected from the group consisting of;
    R10, R11 및 R12는 독립적으로 수소 원자, C1 - C3 알킬, 페닐, 및 벤질기로 이루어진 군에서 선택될 수 있고; R 10 , R 11 and R 12 can be independently selected from the group consisting of hydrogen atom, C 1 -C 3 alkyl, phenyl, and benzyl group;
    R1의 일부로서 포함되는 모든 벤젠기는 독립적으로 C1 - C3 알킬, C1 - C2 할로알킬, 할로겐 원자, 및 시아노기로 이루어진 군에서 선택되는 복수의 치환체를 가질 수 있고; All benzene groups included as part of R 1 may independently have a plurality of substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 2 haloalkyl, a halogen atom, and a cyano group;
    R2, R3, R4, R5, R6, R7, R8 및 R9는 독립적으로 수소 원자, 및 C1 - C3 알킬 중에서 선택될 수 있고; R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 can be independently selected from a hydrogen atom and C 1 -C 3 alkyl;
    R6과 R7, R8과 R9는 독립적으로 카르보닐기로 선택될 수 있고; R 6 and R 7 , R 8 and R 9 can be independently selected from a carbonyl group;
    상기 할로겐이란 불소, 염소 및 브롬 원자로 이루어진 군에서 선택됨.The halogen is selected from the group consisting of fluorine, chlorine and bromine atoms.
  2. 청구항 1에 있어서, 상기 화학식 1의 화합물은 The method of claim 1, wherein the compound of Formula 1
    N-{[1-(2-(1-(페닐아미노카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (1- (phenylaminocarbonyl) -piperazin-4-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Chloromethylbenzamide,
    N-{[1-(2-(1-(p-톨릴아미노카르보닐)-피페라진-4-일)-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (1- (p-tolylaminocarbonyl) -piperazin-4-yl) -ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide,
    N-{[1-(2-(1-(4-클로로페닐아미노카르보닐)-피페라진-4-일)-에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (1- (4-Chlorophenylaminocarbonyl) -piperazin-4-yl) -ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl}- 3-trifluoromethylbenzamide,
    N-{[1-(2-(1-(메톡시카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (1- (methoxycarbonyl) -piperazin-4-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Chloromethylbenzamide,
    N-{[1-(2-(1-(에톡시카르보닐)-피페라진-4-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (1- (ethoxycarbonyl) -piperazin-4-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Chloromethylbenzamide,
    N-{[1-(2-(4-벤조일피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-benzoylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide,
    N-{[1-(2-(4-(2-메틸벤조일)피페라진-1-일)에틸)- 피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (2-methylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide,
    N-{[1-(2-(4-(3-메틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (3-methylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide,
    N-{[1-(2-(4-(4-메틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (4-Methylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide,
    N-{[1-(2-(4-(4-플루오로벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (4-fluorobenzoyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Chloromethylbenzamide,
    N-{[1-(2-(4-(4-시아노벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (4-cyanobenzoyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Chloromethylbenzamide,
    N-{[1-(2-(4-(4-에틸벤조일)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (4-ethylbenzoyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide,
    N-{[1-(2-(4-(페닐술포닐)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (phenylsulfonyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
    N-{[1-(2-(4-프로피오닐피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-propionylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide,
    N-{[1-(2-(4-벤질피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-benzylpiperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide,
    N-{[1-(1-(4-벤조일피페라진-1-일)프로판-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (1- (4-benzoylpiperazin-1-yl) propan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
    N-{[1-(3-(4-벤조일피페라진-1-일)부탄-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (3- (4-benzoylpiperazin-1-yl) butan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
    N-{[1-(2-(4-벤조일피페라진-1-일)프로판-1-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-benzoylpiperazin-1-yl) propan-1-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
    N-{[1-(1-(4-벤조일피페라진-1-일)부탄-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (1- (4- (Benzoylpiperazin-1-yl) butan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
    N-{[1-(2-(4-벤조일피페라진-1-일)부틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-benzoylpiperazin-1-yl) butyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethylbenzamide,
    N-{[1-(2-(4-벤조일피페라진-1-일)-2-메틸프로필)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-benzoylpiperazin-1-yl) -2-methylpropyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
    N-{[1-(1-(4-벤조일피페라진-1-일)-2-메틸프로판-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (1- (4-Benzoylpiperazin-1-yl) -2-methylpropan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3- Trifluoromethylbenzamide,
    N-{[1-(3-(4-(3-클로로페닐)피페라진-1-일)부탄-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (3- (4- (3-chlorophenyl) piperazin-1-yl) butan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide,
    N-{[1-(1-(4-페닐피페라진-1-일)프로판-2-일)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (1- (1- (4-phenylpiperazin-1-yl) propan-2-yl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
    N-{[1-(1-(4-시클로헥실피페라진-1-일)프로판-2-일)-피롤리딘(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (1- (4- (cyclohexylpiperazin-1-yl) propan-2-yl) -pyrrolidin (3R) -yl-carbamoyl] -methyl} -3-trifluoro Methylbenzamide,
    N-{[1-(2-(4-(2-히드록시부틸)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (2-hydroxybutyl) piperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Chloromethylbenzamide,
    N-{[1-(2-(4-(2-히드록시-2-메틸프로필)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (2-hydroxy-2-methylpropyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl}- 3-trifluoromethylbenzamide,
    N-{[1-(2-(4-(2-히드록시-2-페닐에틸)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (2-hydroxy-2-phenylethyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl}- 3-trifluoromethylbenzamide,
    N-{[1-(2-(4-(2-(4-클로로페닐)-2-히드록시에틸)피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (2- (4-chlorophenyl) -2-hydroxyethyl) piperazin-1-yl) ethyl) -pyrrolidin- (3R) -yl-carbamoyl ] -Methyl} -3-trifluoromethylbenzamide,
    N-{[1-(2-(4-벤조일피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-benzoylpiperazin-1-yl) -2-oxoethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
    N-{[1-(2-(4-(4-메틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (4-Methylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide,
    N-{[1-(2-(4-(4-에틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (4-ethylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide,
    N-{[1-(2-(4-(3-메틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (3-Methylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide,
    N-{[1-(2-(4-(2-메틸벤조일)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4- (2-Methylbenzoyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidin- (3R) -yl-carbamoyl] -methyl} -3 Trifluoromethylbenzamide,
    N-{[1-(2-(4-페닐피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, N-{[1- (2- (4-phenylpiperazin-1-yl) -2-oxoethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoromethyl Benzamide,
    N-{[1-(2-(4-(벤족시카르보닐)피페라진-1-일)-2-옥소에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드, 및 N-{[1- (2- (4- (Benzooxycarbonyl) piperazin-1-yl) -2-oxoethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3 -Trifluoromethylbenzamide, and
    N-{[1-(2-(4-벤조일-2,5-디메틸피페라진-1-일)에틸)-피롤리딘-(3R)-일-카바모일]-메틸}-3-트리플루오로메틸벤즈아미드N-{[1- (2- (4-benzoyl-2,5-dimethylpiperazin-1-yl) ethyl) -pyrrolidine- (3R) -yl-carbamoyl] -methyl} -3-trifluoro Rommethylbenzamide
    로 이루어진 군에서 선택된 화합물인 것을 특징으로 하는 화학식 1의 화합물.Compound of Formula 1, characterized in that the compound selected from the group consisting of.
  3. 청구항 1의 화합물의 약학적으로 허용 가능한 염, 광학 이성질체, 수화물, 용매화물 또는 결정다형체.Pharmaceutically acceptable salts, optical isomers, hydrates, solvates or polymorphs of the compound of claim 1.
  4. 청구항 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 CCR2 (chemokine receptor 2) 매개 염증성 질환 및 증상의 예방, 치료 또는 개선용 약학 조성물.A pharmaceutical composition for preventing, treating or ameliorating a chemokine receptor 2 (CCR2) mediated inflammatory disease and condition containing the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  5. 청구항 4에 있어서, The method according to claim 4,
    상기 CCR2 (chemokine receptor 2) 매개 염증성 질환 및 증상은 알레르기성 비염, 호흡기성 알레르기 질환, 만성 폐쇄성 폐질환, 천식, 폐렴, 류마티스성 관절염, 포도막염, 다발성 경화증, 접촉성 피부염, 아토피성 피부염, 크론씨병, 대장염, 신염, 당뇨병, 당뇨 합병증, 비만, 고지혈증, 동맥경화증 및 재협착증으로 이루어진 군으로부터 선택된 것을 특징으로 하는 CCR2 (chemokine receptor 2) 매개 염증성 질환 및 증상의 예방, 치료 또는 개선용 약학 조성물.The CCR2 (chemokine receptor 2) mediated inflammatory diseases and symptoms include allergic rhinitis, respiratory allergic disease, chronic obstructive pulmonary disease, asthma, pneumonia, rheumatoid arthritis, uveitis, multiple sclerosis, contact dermatitis, atopic dermatitis, Crohn's disease, Pharmaceutical composition for the prevention, treatment or amelioration of CCR2 (chemokine receptor 2) mediated inflammatory diseases and symptoms, characterized in that selected from the group consisting of colitis, nephritis, diabetes, diabetes complications, obesity, hyperlipidemia, arteriosclerosis and restenosis.
  6. 청구항 1의 화합물 또는 이의 약학적으로 허용 가능한 염의 혈관보호제 또는 면역억제제로서의 용도.Use of the compound of claim 1, or a pharmaceutically acceptable salt thereof, as an anti-vascular or immunosuppressive agent.
PCT/KR2010/003790 2009-07-10 2010-06-11 Piperazinyl 3-aminopyrrolidine derivatives as a ccr2 antagonist WO2011004972A2 (en)

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RU2012104633/04A RU2012104633A (en) 2009-07-10 2010-06-11 PIPERAZINYL-3-AMINOPYROLRODINE DERIVATIVES AS AN CCON2 ANTAGONIST
BR112012000609A BR112012000609A2 (en) 2009-07-10 2010-06-11 piperazinylethyl 3-aminopyrrolidine derivatives as ccr2 antagonists
CA2767734A CA2767734A1 (en) 2009-07-10 2010-06-11 Piperazinyl 3-aminopyrrolidine derivatives as a ccr2 antagonist
CN201080031168.9A CN102498109B (en) 2009-07-10 2010-06-11 Piperazinyl 3-aminopyrrolidine derivatives as a CCR2 antagonist
US13/383,104 US8575173B2 (en) 2009-07-10 2010-06-11 Piperazinyl 3-aminopyrrolidine derivatives as a CCR2 antagonists
JP2012519459A JP5474189B2 (en) 2009-07-10 2010-06-11 Piperazinylethyl 3-aminopyrrolidine derivative PIPERAZINYL3-AMINOPYRROLIDINEDERIVEVASASACCR2ANTAGONIST} as CCR2 antagonist
EP10797246.5A EP2452939B1 (en) 2009-07-10 2010-06-11 Piperazinyl 3-aminopyrrolidine derivatives as a ccr2 antagonist

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KR101437067B1 (en) * 2012-09-19 2014-09-05 이화여자대학교 산학협력단 Pharmaceutical composition for preventing or treating graft-versus-host disease comprising anti-CXCL2 or anti-CXCR2 monoclonal antibody
CN105878247B (en) * 2014-05-26 2018-11-16 中国医学科学院医药生物技术研究所 Application of the substituted piperazine -1,4- diamide compound in preparation treatment and/or pre- anti-aging medicine
DK3148993T3 (en) 2014-05-28 2019-05-20 Bayer Cropscience Ag PROCEDURE FOR MANUFACTURING THIAZER DERIVATIVES
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